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ArticleNovember 14, 2022

Structure-Based Discovery of Small-Molecule Inhibitors of the Autocatalytic Proliferation of α-Synuclein Aggregates
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Sean Chia
Sean Chia
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
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Z. Faidon Brotzakis
Z. Faidon Brotzakis
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
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Robert I. Horne
Robert I. Horne
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
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Andrea Possenti
Andrea Possenti
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
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Benedetta Mannini
Benedetta Mannini
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
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https://orcid.org/0000-0001-6812-7348
Rodrigo Cataldi
Rodrigo Cataldi
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
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Magdalena Nowinska
Magdalena Nowinska
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
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Roxine Staats
Roxine Staats
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
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Sara Linse
Sara Linse
Department of Biochemistry & Structural Biology, Center for Molecular Protein Science, Lund University, 221 00Lund, Sweden
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https://orcid.org/0000-0001-9629-7109
Tuomas P. J. Knowles
Tuomas P. J. Knowles
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
Department of Physics, Cavendish Laboratory, CambridgeCB3 0HE, U.K.
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https://orcid.org/0000-0002-7879-0140
Johnny Habchi
Johnny Habchi
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
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Michele Vendruscolo*
Michele Vendruscolo
Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
*Email: [email protected]
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https://orcid.org/0000-0002-3616-1610

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Molecular Pharmaceutics

Cite this: Mol. Pharmaceutics 2023, 20, 1, 183–193

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https://doi.org/10.1021/acs.molpharmaceut.2c00548

Published November 14, 2022

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Abstract

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The presence of amyloid fibrils of α-synuclein is closely associated with Parkinson’s disease and related synucleinopathies. It is still very challenging, however, to systematically discover small molecules that prevent the formation of these aberrant aggregates. Here, we describe a structure-based approach to identify small molecules that specifically inhibit the surface-catalyzed secondary nucleation step in the aggregation of α-synuclein by binding to the surface of the amyloid fibrils. The resulting small molecules are screened using a range of kinetic and thermodynamic assays for their ability to bind α-synuclein fibrils and prevent the further generation of α-synuclein oligomers. This study demonstrates that the combination of structure-based and kinetic-based drug discovery methods can lead to the identification of small molecules that selectively inhibit the autocatalytic proliferation of α-synuclein aggregates.

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Introduction

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Parkinson’s disease (PD) is the most common neurogenerative movement disorder, which affects over 6 million individuals worldwide. (1−4) This disease is characterized histopathologically by the accumulation of aberrant deposits known as Lewy bodies, which are composed primarily of the aggregated form of the intrinsically disordered protein α-synuclein. (5,6) Aggregates of α-synuclein, including misfolded oligomers and highly ordered amyloid fibrils, can induce neurotoxicity through a multitude of mechanisms, including cell membrane disruption and mitochondrial damage, which ultimately cause neuronal death. (7−9) In particular, recent evidence implicates prefibrillar α-synuclein oligomeric species in the PD pathology: α-synuclein oligomers appear to specifically interact with the ATP synthase to induce mitochondrial dysfunction, cause early axonal dysfunction, and increase the TLR4-dependent sensitized inflammatory response leading to greater reactive oxygen species (ROS) production. (10−12)

Because of the relevance of α-synuclein aggregates, much effort has been devoted toward the characterization of their structures. (13−17) These structures have enabled the development of structure-based drug discovery approaches, including in particular the identification of peptide-based inhibitors to prevent α-synuclein aggregation. (18,19) Furthermore, binding sites along the surface of α-synuclein fibrils for the development of diagnostics tools have also been identified. (20−23) These developments are relevant considering the current lack of radiotracers for measuring the accumulation of α-synuclein aggregates in the human brain and that such diagnostics tools may eventually enable the presymptomatic diagnosis of synucleinopathies. (20,24−26)

Previous studies have used high-throughput docking approaches to identify α-synuclein fibril-binding compounds. (20−23) However, because of the great technical difficulties in establishing reproducible high-throughput kinetic assays to monitor α-synuclein aggregation, the experimental validation of the compounds predicted from computational screens has been challenging. Recent advances in chemical kinetics approaches have allowed the identification of small molecules and molecular chaperones that are able to inhibit α-synuclein aggregation. (27−30) It has thus been possible to inhibit specifically the surface-catalyzed secondary nucleation step, which is responsible for the autocatalytic proliferation of α-synuclein fibrils, by binding competitively with α-synuclein monomers along specific sites on the surface of α-synuclein fibrils. (27,29) Considering that oligomers are generated primarily by surface-catalyzed secondary nucleation, (31,32) the discovery of compounds targeting this mechanism offers promising opportunities for drug discovery. (28,33) This approach is particularly advantageous as it allows experiments to be performed in a high-throughput manner in 96-well plates, while conferring quantitative analysis of the effect of the compounds on specific microscopic steps in the aggregation process of α-synuclein. These quantitative measurements subsequently enable structure–activity relationship (SAR) studies and facilitate the systematic optimization of the compounds’ properties. (28,33)

In the present study, we identified compounds that bind to α-synuclein fibrils to make advances on two problems: (1) how to prevent the fibril-catalyzed secondary nucleation in the autocatalytic proliferation of α-synuclein fibrils, and (2) how to identify molecular tracers for measuring the accumulation of α-synuclein aggregates through imaging methods. In an initial step toward these goals, we demonstrate the use of an in silico and in vitro combinatorial framework in identifying compounds that bind to α-synuclein fibrils and subsequently inhibit the secondary nucleation process in the aggregation of α-synuclein. In this framework, we first employ a computational method that combines two docking techniques to identify compounds with high predicted binding affinity for α-synuclein fibrils. This list is then validated experimentally through chemical kinetics, which identifies the top compounds that are able to inhibit the surface-catalyzed secondary nucleation step in the aggregation of α-synuclein. The binding affinity of these compounds for α-synuclein fibrils is then validated experimentally.

Overall, this strategy demonstrates the rational development of a combined structure-based and kinetic-based framework to identify compounds that can bind to α-synuclein fibrils and presents an opportunity for the systematic development of compounds that can be potentially used as therapeutic and diagnostic tools for synucleinopathies.

Materials and Methods

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Computational Docking

The docking protocol used in this study comprises four stages. First, we determined a binding site on the α-synuclein fibrils. To achieve this goal, we analyzed a structure of α-synuclein fibrils (PDB ID: 6cu7) using Fpocket, (34) which identifies potential binding pockets based on volume criteria (Figure 3F). We found a pocket in the fibril core (surrounded by residues His50–Lys58 and Thr72–Val77) and a pocket on the fibril surface (surrounded by His50 and Glu57). We focused on the surface binding pocket because the buried binding pocket is unlikely to act as a catalytic site for α-synuclein secondary nucleation. Moreover, α-synuclein secondary nucleation has been reported as significant only below pH 5.8, (35) when histidine residues are protonated, also supporting the choice of the surface binding pocket.

For the selection of screening compounds, we used the ZINC library, which contains a set of over 230 million purchasable compounds for screening. (36) To prioritize the chemical space of small molecules considered in the docking calculations, central nervous system multiparameter optimization (CNS MPO) criteria (37) were applied, effectively reducing the space to ∼2 million compounds. In particular, CNS MPO has been shown to correlate with key in vitro attributes of drug discovery, and thus using this filter potentially enables the identification of compounds with better physicochemical and pharmacokinetic properties pertaining to brain penetration, where α-synuclein is localized. (37) We further subjected these compounds to docking calculation against the binding site identified above using AutoDock Vina. (38) To increase the confidence of the calculations, the top-scoring 10 000 small molecules were selected and docked against the same α-synuclein binding site, using FRED (OpenEye Scientific Software). (39) The top-scoring, common 1000 compounds in both docking protocols are selected and clustered using Tanimoto clustering, (40) leading to a list of 79 clusters.

Preparation of Compounds and Chemicals

The centroids from the above 79 clusters were selected for experimental validation. Compounds were purchased from MolPort (Riga, Latvia), and in the cases for which centroids were not available for purchase, the compounds in the clusters with the closest chemical structures were used as the representative compounds instead. In the end, a total of 67 compounds were purchased (centroids and alternative compounds in 12 clusters were all not available for purchase) and then prepared in DMSO to a stock of 5 mM. All chemicals used were purchased at the highest purity available (>90% in purity).

Preparation of α-Synuclein

Recombinant α-synuclein was purified as described previously. (35,41,42) The plasmid pT7-7 encoding for human α-synuclein was transformed into chemically competent E. coli cells of strain BL21 (DE3)-gold cells (Thermo Scientific). Following transformation, the cells were grown in lysogeny broth (LB) in the presence of ampicillin (100 μg/mL). Cells were induced with isopropyl β-d-1-thiogalactopyranoside (IPTG), grown overnight at 37 °C for 4 h, and harvested by centrifugation in a Beckman Avanti J25 centrifuge with a JA-20 rotor at 5000 rpm (Beckman Coulter, Fullerton, CA). The cell pellet was resuspended in 10 mM Tris, pH 8.0, 1 mM EDTA, 1 mM PMSF and lysed by multiple freeze–thaw cycles and sonication. The cell suspension was boiled for 20 min, and then cooled and centrifuged at 13 500 rpm with a JA-20 rotor (Beckman Coulter). Streptomycin sulfate was added to the supernatant to a final concentration of 10 mg/mL and the mixture was stirred for 15 min at 4 °C. After centrifugation at 13 500 rpm, the supernatant was supplemented with 0.36 g/mL ammonium sulfate. The solution was stirred for 30 min at 4 °C and centrifuged again at 13 500 rpm. The pellet was resuspended in 25 mM Tris, pH 7.7, and ion-exchange chromatography was performed using an HQ/M-column in buffer A (25 mM Tris, pH 7.7) with a linear gradient to buffer B (25 mM Tris, pH 7.7, 600 mM NaCl). The fractions containing α-synuclein (≈300 μM) were dialyzed overnight against the appropriate buffer. The protein concentration was determined from the absorbance at 280 nm using the extinction coefficient ε₂₈₀ = 5600 M^–1 cm^–1.

Preparation of α-Synuclein Fibril Seeds

α-synuclein fibril seeds were produced as described previously. (35,41) Samples of α-synuclein (700 μM) were incubated in 20 mM phosphate buffer (pH 6.5) for 72 h at 40 °C and stirred at 1500 rpm with a Teflon bar on an RCT Basic Heat Plate (IKA, Staufen, Germany). Fibrils were then diluted to 200 μM, aliquoted and flash frozen in liquid nitrogen, and finally stored at −80 °C. For the use of kinetic experiments, the 200 μM fibril stock was thawed and sonicated for 15 s using a tip sonicator (Bandelin, Sonopuls HD 2070, Berlin, Germany), using 10% maximum power and a 50% cycle.

Kinetic Assays

α-synuclein was injected into a Superdex 75 10/300 GL column (GE Healthcare) at a flow rate of 0.5 mL/min and eluted in 20 mM sodium phosphate buffer (pH 4.8) supplemented with 1 mM EDTA. The obtained monomer was diluted in buffer to a desired concentration and supplemented with 50 μM ThT and preformed α-synuclein fibril seeds. The compounds (or DMSO alone) were then added at the desired concentration to a final DMSO concentration of 1% (v/v). Samples were prepared in low-binding Eppendorf tubes and then pipetted into a 96-well half-area, black/clear flat-bottom polystyrene NBS microplate (Corning 3881), 150 μL/well, with three replicates per sample ran in parallel (two replicates in the case of the high-throughput screening in Figure 2). The assay was then initiated by placing the microplate at 37 °C under quiescent conditions in a plate reader (FLUOstar Omega, BMG Labtech, Aylesbury, U.K.). The ThT fluorescence was measured through the bottom of the plate with a 440 nm excitation filter and a 480 nm emission filter.

Transmission Electron Microscopy (TEM)

α-Synuclein samples (10 μM) were prepared and aggregated as described in the kinetic assay, in the absence or presence of 25 μM compound C, without the addition of ThT. Samples were collected from the microplate at the end of the reaction (150 h) into low-binding Eppendorf tubes. They were then prepared on 400-mesh, 3 mm copper grid carbon support film (EM Resolutions Ltd.) and stained with 2% uranyl acetate (wt/vol). The samples were imaged on an FEI Tecnai G₂ transmission electron microscope (Cambridge Advanced Imaging Centre). Images were analyzed using the SIS Megaview II Image Capture system (Olympus).

Determination of the Elongation Rate Constant

In the presence of high concentrations of seeds (≈μM), the aggregation of α-synuclein is dominated by the elongation of the added seeds. Under these where other microscopic processes are negligible, the aggregation kinetics for α-synuclein can be described by (35,41)

{\frac{d M (t)}{d t} |}_{t = 0} = 2 k_{+} P (0) m (0)

where M(t) is the fibril mass concentration at time t, P(0) is the initial number of fibrils, m(0) is the initial monomer concentration, and k₊ is the rate of fibril elongation. In this case, by fitting a line to the early time points of the aggregation reaction as observed by ThT kinetics, 2k₊P(0)m(0) can be calculated for α-synuclein in the absence and presence of the compounds. Subsequently, the elongation rate in the presence of compounds can be expressed as a normalized reduction compared to the elongation rate in the absence of compounds (1% DMSO).

Determination of the Fibril Amplification Rate Constant

In the presence of low concentrations of seeds, the fibril mass fraction M(t) over time was described using a generalized logistic function to the normalized aggregation data (28,43)

\frac{M (t)}{m_{tot}} = 1 - \frac{1}{{[1 + \frac{a}{c} e^{κ t}]}^{c}}

where m_tot denotes the total concentration of α-synuclein monomers. The parameters a and c are defined as

a = \frac{λ^{2}}{2 κ^{2}}

c = \sqrt{\frac{2}{n_{2} (n_{2} + 1)}}

The parameters λ and κ represent combinations for the effective rate constants for primary and secondary nucleation, respectively, and are defined as (28,43)

λ = \sqrt{2 k_{+} k_{n} m_{tot}^{n_{c}}}

κ = \sqrt{2 k_{+} k_{2} m_{tot}^{n_{2} + 1}}

where k_n and k₂ denote the rate constants for primary and secondary nucleation, respectively, and n_c and n₂ denote the reaction orders of primary and secondary nucleation, respectively. In this case, c was fixed at 0.3 for the fitting of all data, and k₂, the amplification rate, is expressed as a normalized reduction for α-synuclein in the presence of the compounds compared to in its absence (1% DMSO). The amplification rate k₂ of α-synuclein denotes the generation of fibrillar aggregates through surface-catalyzed secondary nucleation, where monomers nucleate on the surfaces of α-synuclein fibrils.

Determination of the Oligomer Flux

The prediction of the reactive flux toward oligomers over time was calculated as

ϕ (t) = \frac{1}{r_{+}} \cdot [\frac{m (0)}{m (t)} \cdot \frac{d^{2} M}{d t^{2}} + \frac{1}{m (0)} {(\frac{m (0)}{m (t)} \cdot \frac{d M (t)}{d t})}^{2}]

where r₊= 2k₊m(0) is the apparent elongation rate constant extracted as described earlier and m(0) refers to the total concentration of monomers at the start of the reaction.

Fluorescence Polarization

Compound C (10 μM) was incubated with increasing concentrations of either preformed α-synuclein or Aβ42 fibrils (in 1% DMSO). After incubation, the samples were pipetted into a 96-well half-area, black/clear flat-bottom polystyrene nonbinding surface (NBS) microplate (Corning 3881). The fluorescence polarization of compound C was monitored using a plate reader (CLARIOstar, BMG Labtech, Aylesbury, U.K.) under quiescent conditions at room temperature, using a 360 nm excitation filter and a 430 emission filter. The equilibrium dissociation constant (K_d) was determined by fitting the data to the equation Y = B_max × X/(K_d + X) + NS × X + background using GraphPad Prism software, where B_max denotes the maximum specific binding, NS denotes the slope of nonspecific binding per X unit, and background denotes the amount of nonspecific binding when no ligand is added.

Mass Spectrometry

Preformed α-synuclein fibrils (10 μM) were incubated with 10 μM compound C in 20 mM sodium phosphate buffer (pH 4.8) supplemented with 1 mM EDTA overnight under quiescent conditions at room temperature. The samples were then ultracentrifuged at 100 000g for 30 min, and the supernatant was removed for analysis using a Waters Xevo G2-S QTOF spectrometer (Waters Corporation, MA).

Cell Cultures

Human SH-SY5Y neuroblastoma cells (A.T.C.C., Manassas, VA) were cultured in Dulbecco’s modified Eagle’s medium (DMEM)-F12+GlutaMax supplement (Thermo Fisher Scientific, Waltham, MA) with 10% heat-inactivated fetal bovine serum. The cell cultures were maintained in a 5.0% CO₂ humidified atmosphere at 37 °C and grown until 80% confluence for a maximum of 20 passages.

Colocalization Assay

Samples containing 100 nM (monomer equivalents) α-synuclein fibrils in 20 mM sodium phosphate buffer, pH 4.8, were pre-incubated in the absence or presence of 1 μM compound C in a 96-well plate. The samples were subsequently stained with pFTAA (Amytracker 630 from Ebba Biotech AB, Sweden). Images were acquired using the fluorescence microscope Cytation5 Cell Imaging Reader (BioTek Instruments, Winooski, VT). For the colocalization assay in the presence of cells, the cells were first plated into a 96-well plate and treated for 24 h with the samples containing 100 nM (monomer equivalents) α-synuclein fibrils in 20 mM sodium phosphate buffer, pH 4.8, in the absence or presence of 1 μM compound C. After incubation, the samples were treated in the same procedure as described above.

Results

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Framework to Identify Compounds That Bind α-Synuclein Fibrils

In this work, we describe a framework to identify compounds that bind specific sites on the surface of α-synuclein fibrils and are able to block the process of fibril-catalyzed secondary nucleation. This method consists of a computational docking approach to identify small-molecule candidates from a large library of compounds, and a subsequent in vitro approach based on chemical kinetics to assess the ability of the candidates to inhibit the aggregation of α-synuclein, as well as their affinity toward α-synuclein fibrils (Figure 1).

Figure 1. Combined structure-based and kinetic-based approach to identify small molecules that bind α-synuclein fibrils and inhibit its aggregation. In the first step, computational docking is performed on a large library of small molecules. The top candidates are then clustered to identify a subset of chemically diverse compounds that exhibit high predicted binding scores for α-synuclein fibrils. Subsequently, these compounds are experimentally validated through a kinetic assay for their ability to inhibit the secondary nucleation aggregation of α-synuclein by binding to the surface of fibrils. Further rate constant analysis and fibril-binding experiments allow for the positive compounds to be characterized based on both their inhibition of the kinetic assay, as well as their binding affinity toward α-synuclein fibrils.

First, from a library of compounds, small molecules are individually docked against a binding pocket chosen along the groove of the fibril (Materials and Methods section). This groove, which involves residues His50 and Glu57, was selected as the potential site for docking since its geometry, position and physicochemical properties identified it as a likely catalytic site for α-synuclein secondary nucleation (Figure 1 and Materials and Methods section). Using the predicted binding scores (ΔG_b) as the parameter for ranking the compounds, the docking procedure generated a list of top 1000 candidates. As a means of increasing the chemical diversity of the compounds to be experimentally validated, a clustering method based on the chemical similarity of the compounds was adopted, in which the centroids of each of the clusters were selected as the final candidates of the library of compounds to be tested in vitro (Figure 1).

Next, these centroid compounds were validated experimentally using a chemical kinetics-based assay of α-synuclein aggregation. Specifically, in the presence of low amounts of preformed seeds and at mildly acidic pH, the aggregation of α-synuclein is dominated by a surface-catalyzed secondary nucleation process, in which monomers form nuclei along the fibril surfaces. (31) This autocatalytic process results in the rapid generation of aggregates that then elongate to form α-synuclein fibrils. When the aggregation of α-synuclein is performed in the presence of compounds with suitable binding affinity for the surface of the α-synuclein fibrils, this results in a decreased amplification rate of α-synuclein aggregates. (27,29)

The small-molecule inhibitors identified in this way were further validated for their binding affinity toward α-synuclein fibrils using fluorescence polarization and mass-spectrometry-based pull-down assays. Overall, using this framework, small-molecule candidates could be characterized through their predicted and experimental binding affinity, as well as their kinetic inhibitory properties as a result of their interaction with α-synuclein fibrils.

In Silico Docking of Compounds Predicted to Bind α-Synuclein Fibrils

Using AutoDock Vina (38) and FRED, (39) a wide distribution of binding scores was observed for compounds in the ZINC library (Materials and Methods). (36) When assessing the top 10 000 compounds with the highest binding affinity, we observed a wider distribution of binding scores using FRED (−4 to −14 kcal/mol) than AutoDock Vina (−6.6 to −8.6 kcal/mol) (Figure S1). We also found that the predicted binding scores did not correlate strongly between the two methods (Figure S1). Such differences in the predicted scores can be attributed to the different scoring functions used among docking methods, leading to the choice of consensus compounds. (44) Thus, we selected the top 10% (1000 common compounds) of the candidates with a high predicted binding score in both methods (Figure S1). The candidate library was further refined by employing a clustering method based on the chemical structures of the compounds to identify the centroids of each cluster as the representative compound in the cluster. Although this procedure may result in a lower number of hits due to the exclusion of chemical derivatives of a potential α-synuclein fibril binder that are clustered together, it also increases the chemical diversity of the library set, and therefore allows the sampling of a wider chemical space to screen for potential fibril binders.

Identification of Compounds That Inhibit α-Synuclein Secondary Nucleation

From the library of centroids, we selected 67 compounds for experimental validation in terms of their binding affinity toward α-synuclein fibrils (Materials and Methods section). In particular, compounds were screened for their potency against 10 μM α-synuclein, which is relatively close to the estimated physiological concentration of α-synuclein in the neuronal synapse (≈50 μM). (45) Out of the 67 compounds tested, five compounds were found to inhibit α-synuclein aggregation (Figure 2). The compounds were found to inhibit the aggregation of α-synuclein to different extents. In particular, three of the compounds (A, B, and E) showed moderate potency, increasing the half-time (t_1/2) of the aggregation by 1.5 times, while compounds C and D exhibited stronger potency by increasing the t_1/2 of the aggregation by 3.5 and 3 times, respectively. We also found that the chemical structures of these inhibitors tend to involve aromatic moieties (Figure 2C). More specifically, the aromatic regions of these compounds appeared within close proximity to the residues along the groove of the α-synuclein fibrils, suggesting that interactions could be established between the compounds and α-synuclein through these regions (Figure 3). Furthermore, we also observed a high similarity in terms of the compound positions within the selected groove of α-synuclein fibrils between using docking methods, thus suggesting that the binding of these compounds to the α-synuclein fibrils may involve specific interactions, which are likely to be a combination of electrostatic and nonpolar nature (Figure 3). Despite this observation, we also note the variety of polymorphic α-synuclein fibril structures that have been reported, which can differ in their structure, or the assembly of the protofilaments. (13−17) Such diversity in the structural features of the α-synuclein fibrils formed may have contributed to the lower hit rate of compounds obtained from the in silico docking. Thus, further optimization by docking compounds across multiple polymorphic structures reported may increase the hit rate of positive compounds that are able to inhibit the aggregation of α-synuclein. A recent study has shown that the structures of α-synuclein fibrils derived from PD patients are different from the one used in this study. (46) We anticipate that the approach that we describe in this work will be applicable to these new fibril structures, once an in vitro assay capable of reproducing them will be developed.

Figure 2. Five compounds selected from the docking library inhibit the aggregation of α-synuclein. (A) Kinetic profiles of a 10 μM solution of α-synuclein in the presence of 25 nM seeds at pH 4.8 and 37 °C, in the presence of 1% DMSO alone (beige), in the presence of 10 molar equivalents of compounds A–E (represented in different colors), or in the presence of 10 molar equivalents of other compounds in the docking library that did not affect significantly α-synuclein aggregation (black). (B) Relative t_1/2 of the aggregation of α-synuclein in the presence of compounds A–E as shown in (A), normalized to the DMSO control. (C) Chemical structures of compounds A–E. Throughout, error bars represent mean ± SEM of two replicates.

Figure 3. Computational docking of compounds to α-synuclein fibrils. (A–E) Binding poses of compounds A–E to the selected binding pocket in α-synuclein fibrils (centered between residues His50 and Glu57), determined either through FRED or AutoDock Vina. (F) Representation of possible binding pockets in the fibril structure (PDB: 6cu7, cyan) identified by Fpocket, with pockets in the fibril core (blue spheres), and at the fibril surface (red spheres). Key binding site residues His50 and Glu57 are shown in licorice representation.

To rule out potential effects whereby the compounds inhibit the aggregation of α-synuclein by stabilizing nonfibrillar aggregates, we used transmission electron microscopy (TEM) to image the α-synuclein species formed at the end of the aggregation reaction in the absence and presence of compound C (Figure S2). These measurements showed the presence of α-synuclein fibrils at the end of the aggregation process both in the absence and presence of compound C, suggesting that the compounds that we identified are able to delay the aggregation process without redirecting it toward the formation of nonfibrillar α-synuclein aggregates (Figure S2).

Kinetic Analysis of α-Synuclein Aggregation in the Presence of the Inhibitors

To characterize the inhibitory potency of the five compounds against the aggregation of α-synuclein, we measured the secondary nucleation process of α-synuclein in the presence of varying compound concentrations, from substoichiometric ratios (0.625 molar equivalents) to overstoichiometric ratios (5 molar equivalents) (Figures 4A and S3–S5). For all of the five compounds, we observed a dose-dependent inhibition in the aggregation of α-synuclein, resulting in a systematic increase in the t_1/2 of aggregation. Similarly to what we observed in the preliminary screening, the potency of the compounds varied between compounds A, B, and E, which exhibited a weaker effect, and compounds C and D, which had a stronger effect (Figures 4A and S3–S5). We further quantified the effect of the compounds, finding that they were able to significantly inhibit the rate of fibril amplification. This mechanism of action redirects the overall reactive flux toward elongation events, thus promoting the formation of fibrils of longer dimensions instead. (47) We obtained these results by fitting the experimental data with a logistic function describing the amplification of α-synuclein aggregates over time (Materials and Methods section) (Figure 4B). These compounds are likely to compete with α-synuclein monomers on the nucleation sites, as shown previously with other compounds and molecular chaperones that also exhibit inhibition of secondary nucleation processes. (27,29,47,48)

Figure 4. Compounds identified by docking specifically inhibit the proliferation of α-synuclein aggregates by secondary nucleation. (A) Kinetic profiles of a 10 μM solution of α-synuclein in the presence of 25 nM seeds at pH 4.8, 37 °C, in the presence of either 1% DMSO alone (purple) or increasing molar equivalents of compound C (represented in different colors). (B) Relative rate of fibril amplification of α-synuclein in the presence of compounds A–E as shown in (A) and Figure S3, normalized to the DMSO control. (C) Kinetic profiles of a 10 μM solution of α-synuclein in the presence of 5 μM seeds at pH 4.8, 37 °C, in the presence of either 1% DMSO alone (purple) or increasing molar equivalents of compound C (represented in different colors). Dotted lines indicate the v_max of the reaction which is used to extract the elongation rate of the aggregation process. (D) Relative rate of fibril elongation of α-synuclein in the presence of compounds A–E as shown in (C) and Figure S5,6, normalized to the DMSO control. Throughout, error bars represent mean ± SEM of three replicates.

The potency in inhibiting the amplification rate of the compounds was found to be in the order C > D > B and E > A. For instance, at 2.5 molar equivalents, while compounds C and D were able to inhibit the amplification rate of α-synuclein by 87 and 65%, respectively, compounds B and E were only able to inhibit this rate by 27 and 12%, respectively, and compound A was not able to significantly inhibit this process at this molar equivalent concentration.

To further probe the mechanism by which the compounds inhibit the aggregation process of α-synuclein, we also measured the aggregation process of α-synuclein in the absence and presence of the compounds with the addition of high concentration of preformed α-synuclein fibril seeds (Figures 4C, S5, and S6). Under such conditions, the aggregation process of α-synuclein proceeds as an exponential rather than sigmoidal function, indicative of an aggregation mechanism dominated by elongation processes with negligible contribution of secondary nucleation (35,41) (Figure 4C). This phenomenon can be ascribed to a large number of growth-competent ends of fibrils present at the start of the aggregation process for further monomer addition. We observed that, under such conditions, the elongation rate, and consequently the aggregation process, was not significantly perturbed by the presence of the compounds (Figures 4C,D, S5, and S6). Thus, the inhibition, as observed using the low-seed aggregation assay, is likely due to the inhibition of the secondary nucleation process rather than the elongation process (Figures 4A, S3). Experimentally, the lack of significant effects on both the rate and amplitude of fluorescence emitted in the ThT-based assay under the high-seed conditions suggests that the compounds do not interfere with the fluorescence of ThT itself, and the inhibition as observed from the low-seed aggregation assay is likely to be a specific perturbation in the aggregation of α-synuclein (Figure S5). This also indicates that the compounds that were identified using our approach are likely binding the surface of α-synuclein fibrils, rather than the ends, further supporting their binding to the selected groove. Finally, compounds previously found to interact directly with α-synuclein monomers have been shown to interfere with all microscopic steps in the aggregation process, i.e., secondary nucleation and elongation, as the concentration of free α-synuclein is reduced. (49) Since the five compounds identified here do not affect greatly the elongation process, their interaction with α-synuclein monomers is unlikely to be significant. Further insights into their mechanism of action could be obtained from more extensive structural studies, particularly at different pH conditions, which also alters the significance of secondary nucleation in the overall aggregation process of α-synuclein. (35)

Compound C Inhibits α-Synuclein Oligomer Formation

The reactive flux toward α-synuclein oligomers in the aggregation reaction of α-synuclein is governed by multiple processes, including crucially secondary nucleation. (31) By extracting the change in the amplification rate due to the presence of the compounds, and by accounting for the specific inhibition of the secondary nucleation process rather than the elongation process, we can calculate the reactive flux toward oligomers over time in the absence and presence of increasing concentrations of the compounds (Figures 5A and S7) (Materials and Methods section). Depending on their potency, we observed that compounds were able to delay the rate of reactive flux toward oligomers, as well as a delay in the overall formation of oligomers over time (integral area of flux). (28,33) Future studies will be required to experimentally validate this drop in the reactive flux toward oligomers, as demonstrated for anti-Aβ antibodies previously using a combination of size-exclusion chromatography and mass spectrometry. (50)

Figure 5. Compound C inhibits the reactive flux toward α-synuclein oligomers and displays binding affinity and specificity toward α-synuclein fibrils. (A) Time dependence of the reactive flux toward α-synuclein oligomers either in the presence of 1% DMSO alone (purple) or in the presence of increasing molar equivalents of compound C (represented in different colors), normalized to the DMSO control. (B) Change in fluorescence polarization (in mP units) of 10 μM compound C with increasing concentrations of either α-synuclein fibrils (purple) or Aβ42 fibrils (red). The solid lines are fits to the points using a one-step binding curve, estimating a K_d of 4 μM for compound C toward α-synuclein fibrils. (C) Total ion current (TIC) of 10 μM compound C bound and unbound to 10 μM α-synuclein fibrils detected by mass spectrometry (see the Materials and Methods section). (D) Representative images indicating either the fluorescence of the red channel (amyloid-specific dye pFTAA) or the green channel (compound C) following incubation in the absence (top) or presence (bottom) of 100 nM α-synuclein fibrils. Throughout, error bars represent mean ± SEM of two replicates.

Compound C Binds α-Synuclein Fibrils

As a validation of the binding of these candidates to the surface of α-synuclein fibrils, we also performed fluorescence polarization experiments of compound C, the strongest inhibitor of all of the positive compounds, in the presence of increasing concentrations of α-synuclein fibrils (Figures 5B and S7). Additionally, since compound C exhibits a high degree of intrinsic fluorescence, fluorescence polarization measurements allowed us to determine the proportion of bound and unbound fractions of compound C toward α-synuclein fibrils (Figure S8). We observed a dose-dependent increase in the polarization (a unit-less property) of compound C as a function of increasing concentrations of α-synuclein fibrils. By fitting this response as a function of the concentration of α-synuclein fibrils, the apparent dissociation constant (K_d) was found to be about 4 μM (Figure 5B) (Materials and Methods section). However, we note that the K_d value obtained is based on the concentration of α-synuclein fibrils in monomer equivalents. Since α-synuclein fibrils tend to contain at least 200 monomers per unit, (35) it is thus likely that the actual K_d value (in terms of number of fibrillar units) should be significantly lower, considering the binding of compound C targets a distinct groove within α-synuclein fibrils rather than amino acid sequences within individual monomeric subunits (Figure 3C).

To test for the specificity of compound C for α-synuclein fibrils, we measured the change in polarization upon incubation of compound C with Aβ42 fibrils, which are associated with Alzheimer’s disease (Figure 5B). In this case, we observed a much lower increase in the polarization, as only a slight increase could be measured at 10 μM Aβ42 fibrils. This result suggests that compound C binds specifically to the surface of α-synuclein fibrils, as predicted from the docking, rather than having generic nonspecific interactions with hydrophobic aggregates (Figure 5B).

To further support the fluorescence polarization data, we also performed a mass-spectrometry-based pull-down assay to assess the amounts of compound bound to α-synuclein fibrils (Figure 5C) (Materials and Methods section). We found that ∼40% of compound C was still associated with α-synuclein fibrils after an ultracentrifugation pull-down (Figure 5C). Finally, we sought to explore the potential use of compound C as a fluorescent probe of α-synuclein fibrils. In this experiment, fluorescent images of α-synuclein fibrils were acquired after incubation with compound C (through the green channel) or the amyloid-specific fluorescence dye pFTAA (through the red channel) (Figure 5D). We observed a distinct overlap of the fluorescence between both channels, demonstrating the colocalization of compound C with the α-synuclein fibrils (stained by pFTAA). This confirms the significant affinity of compound C toward α-synuclein fibrils as previously shown through chemical kinetics. We further visualized the colocalization of compound C with exogenous α-synuclein fibrils in the presence of neuroblastoma cells (Figure S9). Indeed, the same behavior manifested as well, suggesting the higher specific affinity of compound C toward the α-synuclein aggregates over other cellular material. This also shows the potential use of such compounds in biological studies involving α-synuclein aggregation.

Discussion

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In this work, we have reported the use of a structure-based approach to identify small molecules whose mechanism of action is to bind α-synuclein fibrils and inhibit the secondary nucleation step in the autocatalytic proliferation of α-synuclein aggregates. We anticipate that such an approach will enable the rational design and systematic development of small molecules capable of binding specific sites with different properties on α-synuclein fibrils of different morphologies, as well as in fibrils formed by other disease-related proteins, thereby creating new opportunities in the diagnostics and therapeutics for protein misfolding diseases.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.2c00548.

Predicted binding affinity of compounds via computational docking; TEM images of α-synuclein fibrils formed in the presence of molecules; kinetic profiles of α-synuclein aggregation in the presence of molecules; time dependence of reactive flux toward α-synuclein oligomers in the presence of molecules; fluorescence emission spectra of molecule C; colocalization of molecules with α-synuclein fibrils in the presence of neuroblastoma cells; list of all molecules from docking studies experimentally validated; and supplementary methods, supplementary figures, and supplementary table (PDF)

mp2c00548_si_001.pdf (1.58 MB)

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Author Information

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Corresponding Author
- Michele Vendruscolo - Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.; https://orcid.org/0000-0002-3616-1610; Email: [email protected]
Authors
- Sean Chia - Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.; Present Address: Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore
- Z. Faidon Brotzakis - Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
- Robert I. Horne - Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
- Andrea Possenti - Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
- Benedetta Mannini - Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.; https://orcid.org/0000-0001-6812-7348
- Rodrigo Cataldi - Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
- Magdalena Nowinska - Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
- Roxine Staats - Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
- Sara Linse - Department of Biochemistry & Structural Biology, Center for Molecular Protein Science, Lund University, 221 00Lund, Sweden; https://orcid.org/0000-0001-9629-7109
- Tuomas P. J. Knowles - Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.; Department of Physics, Cavendish Laboratory, CambridgeCB3 0HE, U.K.; https://orcid.org/0000-0002-7879-0140
- Johnny Habchi - Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Funding
The authors acknowledge support from the Agency for Science, Technology, and Research, Singapore (S.C.); the Department of Chemistry and the Centre for Misfolding Diseases of the University of Cambridge (S.C., Z.F.B., R.I.H., A.P., B.M., R.C., M.N., R.S., T.P.J.K., J.H., M.V.); the Swedish Research Concil (S.L.); the Frances and Augustus Newman Foundation (T.P.J.K.); the UK Biotechnology and Biochemical Sciences Research Council (M.V.); and the Wellcome Trust (T.P.J.K. and M.V.).
Notes
The authors declare the following competing financial interest(s): Sara Linse, Tuomas P. J. Knowles, Johnny Habchi and Michele Vendruscolo are founders of Wren Therapeutics. Andrea Possenti, Benedetta Mannini, Roxine Staats are currently employees of Wren Therapeutics. Sean Chia and Rodrigo Cataldi have been employees of Wren Therapeutics. Robert I. Horne is a consultant for Wren Therapeutics Magdalena Nowinska has been a consultant for Wren Therapeutics.

Abbreviations

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K_d	apparent dissociation constant
SAR	structure–activity relationship
TEM	transmission electron microscopy

References

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A review. The distinct protein aggregates that are found in Alzheimer's, Parkinson's, Huntington's and prion diseases seem to cause these disorders. Small intermediates - sol. oligomers - in the aggregation process can confer synaptic dysfunction, whereas large, insol. deposits might function as reservoirs of the bioactive oligomers. These emerging concepts are exemplified by Alzheimer's disease, in which amyloid β-protein oligomers adversely affect synaptic structure and plasticity. Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.
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Prots, I.; Grosch, J.; Brazdis, R. M.; Simmnacher, K.; Veber, V.; Havlicek, S.; Hannappel, C.; Krach, F.; Krumbiegel, M.; Schütz, O.; Reis, A.; Wrasidlo, W.; Galasko, D. R.; Groemer, T. W.; Masliah, E.; Schlötzer-Schrehardt, U.; Xiang, W.; Winkler, J.; Winner, B. α-Synuclein Oligomers Induce Early Axonal Dysfunction in Human IPSC-Based Models of Synucleinopathies. Proc. Natl. Acad. Sci. U.S.A. 2018, 115, 7813– 7818, DOI: 10.1073/pnas.1713129115
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α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies
Prots, Iryna; Grosch, Janina; Brazdis, Razvan-Marius; Simmnacher, Katrin; Veber, Vanesa; Havlicek, Steven; Hannappel, Christian; Krach, Florian; Krumbiegel, Mandy; Schuetz, Oliver; Reis, Andre; Wrasidlo, Wolfgang; Galasko, Douglas R.; Groemer, Teja W.; Masliah, Eliezer; Schloetzer-Schrehardt, Ursula; Xiang, Wei; Winkler, Juergen; Winner, Beate
Proceedings of the National Academy of Sciences of the United States of America (2018), 115 (30), 7813-7818CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
α-Synuclein (α-Syn) aggregation, proceeding from oligomers to fibrils, is one central hallmark of neurodegeneration in synucleinopathies. α-Syn oligomers are toxic by triggering neurodegenerative processes in in vitro and in vivo models. However, the precise contribution of α-Syn oligomers to neurite pathol. in human neurons and the underlying mechanisms remain unclear. Here, we demonstrate the formation of oligomeric α-Syn intermediates and reduced axonal mitochondrial transport in human neurons derived from induced pluripotent stem cells (iPSC) from a Parkinson's disease patient carrying an α-Syn gene duplication. We further show that increased levels of α-Syn oligomers disrupt axonal integrity in human neurons. We apply an α-Syn oligomerization model by expressing α-Syn oligomer-forming mutants (E46K and E57K) and wild-type α-Syn in human iPSC-derived neurons. Pronounced α-Syn oligomerization led to impaired anterograde axonal transport of mitochondria, which can be restored by the inhibition of α-Syn oligomer formation. Furthermore, α-Syn oligomers were assocd. with a subcellular relocation of transport-regulating proteins Miro1, KLC1, and Tau as well as reduced ATP levels, underlying axonal transport deficits. Consequently, reduced axonal d. and structural synaptic degeneration were obsd. in human neurons in the presence of high levels of α-Syn oligomers. Together, increased dosage of α-Syn resulting in α-Syn oligomerization causes axonal transport disruption and energy deficits, leading to synapse loss in human neurons. This study identifies α-Syn oligomers as the crit. species triggering early axonal dysfunction in synucleinopathies.
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Ludtmann, M. H. R.; Angelova, P. R.; Horrocks, M. H.; Choi, M. L.; Rodrigues, M.; Baev, A. Y.; Berezhnov, A. V.; Yao, Z.; Little, D.; Banushi, B.; Al-Menhali, A. S.; Ranasinghe, R. T.; Whiten, D. R.; Yapom, R.; Dolt, K. S.; Devine, M. J.; Gissen, P.; Kunath, T.; Jaganjac, M.; Pavlov, E. V.; Klenerman, D.; Abramov, A. Y.; Gandhi, S. α-Synuclein Oligomers Interact with ATP Synthase and Open the Permeability Transition Pore in Parkinson’s Disease. Nat. Commun. 2018, 9, 2293 DOI: 10.1038/s41467-018-04422-2
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α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease
Ludtmann Marthe H R; Angelova Plamena R; Abramov Andrey Y; Ludtmann Marthe H R; Horrocks Mathew H; Rodrigues Margarida; Ranasinghe Rohan T; Whiten Daniel R; Klenerman David; Horrocks Mathew H; Horrocks Mathew H; Choi Minee L; Yao Zhi; Gandhi Sonia; Choi Minee L; Yao Zhi; Gandhi Sonia; Baev Artyom Y; Berezhnov Alexey V; Little Daniel; Banushi Blerida; Devine Michael J; Gissen Paul; Al-Menhali Afnan Saleh; Jaganjac Morana; Yapom Ratsuda; Dolt Karamjit Singh; Kunath Tilo; Devine Michael J; Pavlov Evgeny V; Klenerman David
Nature communications (2018), 9 (1), 2293 ISSN:.
Protein aggregation causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric α-synuclein improves ATP synthase efficiency. Here, we report that aggregation of monomers generates beta sheet-rich oligomers that localise to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric α-synuclein impairs complex I-dependent respiration. Oligomers induce selective oxidation of the ATP synthase beta subunit and mitochondrial lipid peroxidation. These oxidation events increase the probability of permeability transition pore (PTP) opening, triggering mitochondrial swelling, and ultimately cell death. Notably, inhibition of oligomer-induced oxidation prevents the pathological induction of PTP. Inducible pluripotent stem cells (iPSC)-derived neurons bearing SNCA triplication, generate α-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of α-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson's disease.
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Hughes, C. D.; Choi, M. L.; Ryten, M.; Hopkins, L.; Drews, A.; Botía, J. A.; Iljina, M.; Rodrigues, M.; Gagliano, S. A.; Gandhi, S.; Klenerman, D.; Bryant, C. Picomolar Concentrations of Oligomeric Alpha - Synuclein Sensitizes TLR4 to Play an Initiating Role in Parkinson’ s Disease Pathogenesis. Acta Neuropathol. 2019, 137, 103– 120, DOI: 10.1007/s00401-018-1907-y
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Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson's disease pathogenesis
Hughes, Craig D.; Choi, Minee L.; Ryten, Mina; Hopkins, Lee; Drews, Anna; Botia, Juan A.; Iljina, Maria; Rodrigues, Magarida; Gagliano, Sarah A.; Gandhi, Sonia; Bryant, Clare; Klenerman, David
Acta Neuropathologica (2019), 137 (1), 103-120CODEN: ANPTAL; ISSN:0001-6322. (Springer)
Despite the wealth of genomic and transcriptomic data in Parkinson's disease (PD), the initial mol. events are unknown. Using LD score regression anal., we show significant enrichment in PD heritability within regulatory sites for LPS-activated monocytes and that TLR4 expression is highest within human substantia nigra, the most affected brain region, suggesting a role for TLR4 inflammatory responses. We then performed extended incubation of cells with physiol. concns. of small alpha-synuclein oligomers observing the development of a TLR4-dependent sensitized inflammatory response with time, including TNF-α prodn. ROS and cell death in primary neuronal cultures were significantly reduced by TLR4 antagonists revealing that an indirect inflammatory mechanism involving cytokines produced by glial cells makes a major contribution to neuronal death. Prolonged exposure to low levels of alpha-synuclein oligomers sensitizes TLR4 responsiveness in astrocytes and microglial, explaining how they become pro-inflammatory, and may be an early causative event in PD.
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Li, B.; Ge, P.; Murray, K. A.; Sheth, P.; Zhang, M.; Nair, G.; Sawaya, M. R.; Shin, W. S.; Boyer, D. R.; Ye, S.; Eisenberg, D. S.; Zhou, Z. H.; Jiang, L. Cryo-EM of Full-Length α-Synuclein Reveals Fibril Polymorphs with a Common Structural Kernel. Nat. Commun. 2018, 9, 3609 DOI: 10.1038/s41467-018-05971-2
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Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel
Li Binsen; Sheth Phorum; Nair Gayatri; Shin Woo Shik; Jiang Lin; Ge Peng; Ye Shulin; Zhou Z Hong; Murray Kevin A; Zhang Meng; Sawaya Michael R; Boyer David R; Eisenberg David S; Zhou Z Hong
Nature communications (2018), 9 (1), 3609 ISSN:.
α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and in vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn fibrils differ in atomic structure remains elusive. Here, we present fibril polymorphs from the full-length recombinant human aSyn and their seeding capacity and cytotoxicity in vitro. By cryo-electron microscopy helical reconstruction, we determine the structures of the two predominant species, a rod and a twister, both at 3.7 ÅA resolution. Our atomic models reveal that both polymorphs share a kernel structure of a bent β-arch, but differ in their inter-protofilament interfaces. Thus, different packing of the same kernel structure gives rise to distinct fibril polymorphs. Analyses of disease-related familial mutations suggest their potential contribution to the pathogenesis of synucleinopathies by altering population distribution of the fibril polymorphs. Drug design targeting amyloid fibrils in neurodegenerative diseases should consider the formation and distribution of concurrent fibril polymorphs.
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Guerrero-Ferreira, R.; Taylor, N. M. I.; Mona, D.; Ringler, P.; Lauer, M. E.; Riek, R.; Britschgi, M.; Stahlberg, H. Cryo-EM Structure of Alpha-Synuclein Fibrils. eLife 2018, 7, e36402 DOI: 10.7554/eLife.36402
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Cryo-EM structure of alpha-synuclein fibrils
Guerrero-Ferreira, Ricardo; Taylor, Nicholas M. I.; Mona, Daniel; Ringler, Philippe; Lauer, Matthias E.; Riek, Roland; Britschgi, Markus; Stahlberg, Henning
eLife (2018), 7 (), e36402/1-e36402/18CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
Parkinson's disease is a progressive neuropathol. disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concns. in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), detd. by cryo-electron microscopy at a resoln. of 3.4 Å . Two protofilaments form a polar fibril composed of staggered b-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, contg. three of the mutation sites assocd. with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of mols. for diagnosis and treatment of synucleinopathies.
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Li, Y.; Zhao, C.; Luo, F.; Liu, Z.; Gui, X.; Luo, Z.; Zhang, X.; Li, D.; Liu, C.; Li, X. Amyloid Fibril Structure of α-Synuclein Determined by Cryo-Electron Microscopy. Cell Res. 2018, 28, 897– 903, DOI: 10.1038/s41422-018-0075-x
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Amyloid fibril structure of α-synuclein determined by cryo-electron microscopy
Li, Yaowang; Zhao, Chunyu; Luo, Feng; Liu, Zhenying; Gui, Xinrui; Luo, Zhipu; Zhang, Xiang; Li, Dan; Liu, Cong; Li, Xueming
Cell Research (2018), 28 (9), 897-903CODEN: CREEB6; ISSN:1001-0602. (Nature Research)
α-Synuclein (α-syn) amyloid fibrils are the major component of Lewy bodies, which are the pathol. hallmark of Parkinson's disease (PD) and other synucleinopathies. High-resoln. structure of α-syn fibril is important for understanding its assembly and pathol. mechanism. Here, we detd. a fibril structure of full-length α-syn (1-140) at the resoln. of 3.07 Å by cryo-electron microscopy (cryo-EM). The fibrils are cytotoxic, and transmissible to induce endogenous α-syn aggregation in primary neurons. Based on the reconstructed cryo-EM d. map, we were able to unambiguously build the fibril structure comprising residues 37-99. The α-syn amyloid fibril structure shows two protofilaments intertwining along an approx. 21 screw axis into a left-handed helix. Each protofilament features a Greek key-like topol. Remarkably, five out of the six early-onset PD familial mutations are located at the dimer interface of the fibril (H50Q, G51D, and A53T/E) or involved in the stabilization of the protofilament (E46K). Furthermore, these PD mutations lead to the formation of fibrils with polymorphic structures distinct from that of the wild-type. Our study provides mol. insight into the fibrillar assembly of α-syn at the at. level and sheds light on the mol. pathogenesis caused by familial PD mutations of α-syn.
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Rodriguez, J. A.; Ivanova, M. I.; Sawaya, M. R.; Cascio, D.; Reyes, F. E.; Shi, D.; Sangwan, S.; Guenther, E. L.; Johnson, L. M.; Zhang, M.; Jiang, L.; Arbing, M. A.; Nannenga, B. L.; Hattne, J.; Whitelegge, J.; Brewster, A. S.; Messerschmidt, M.; Boutet, S.; Sauter, N. K.; Gonen, T.; Eisenberg, D. S. Structure of the Toxic Core of α-Synuclein from Invisible Crystals. Nature 2015, 525, 486– 490, DOI: 10.1038/nature15368
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Structure of the toxic core of α-synuclein from invisible crystals
Rodriguez, Jose A.; Ivanova, Magdalena I.; Sawaya, Michael R.; Cascio, Duilio; Reyes, Francis E.; Shi, Dan; Sangwan, Smriti; Guenther, Elizabeth L.; Johnson, Lisa M.; Zhang, Meng; Jiang, Lin; Arbing, Mark A.; Nannenga, Brent L.; Hattne, Johan; Whitelegge, Julian; Brewster, Aaron S.; Messerschmidt, Marc; Boutet, Sebastien; Sauter, Nicholas K.; Gonen, Tamir; Eisenberg, David S.
Nature (London, United Kingdom) (2015), 525 (7570), 486-490CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
α-Synuclein is the main component of Lewy bodies, the neuron-assocd. aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which the authors term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here, the authors describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure detn. by synchrotron x-ray diffraction, the authors used micro-electron diffraction to det. the structure at at. resoln. The 1.4-Å-resoln. structure demonstrated that this method can det. previously unknown protein structures and here yielded, to the authors' knowledge, the highest resoln. achieved by any cryo-electron microscopy method to date. The structure exhibited protofibrils built of pairs of face-to-face β-sheets. X-ray fiber diffraction patterns showed the similarity of NACore to toxic fibrils of full-length α-synuclein. The NACore structure, together with that of a 2nd segment, inspired a model for most of the ordered portion of the toxic, full-length α-synuclein fibril, presenting opportunities for the design of inhibitors of α-synuclein fibrils.
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Schweighauser, M.; Shi, Y.; Tarutani, A.; Kametani, F.; Murzin, A. G.; Ghetti, B.; Matsubara, T.; Tomita, T.; Ando, T.; Hasegawa, K.; Murayama, S.; Yoshida, M.; Hasegawa, M.; Scheres, S. H. W.; Goedert, M. Structures of α-Synuclein Filaments from Multiple System Atrophy. Nature 2020, 585, 464– 469, DOI: 10.1038/s41586-020-2317-6
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Structures of α-synuclein filaments from multiple system atrophy
Schweighauser, Manuel; Shi, Yang; Tarutani, Airi; Kametani, Fuyuki; Murzin, Alexey G.; Ghetti, Bernardino; Matsubara, Tomoyasu; Tomita, Taisuke; Ando, Takashi; Hasegawa, Kazuko; Murayama, Shigeo; Yoshida, Mari; Hasegawa, Masato; Scheres, Sjors H. W.; Goedert, Michel
Nature (London, United Kingdom) (2020), 585 (7825), 464-469CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
Synucleinopathies, which include multiple system atrophy (MSA), Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases1. Existing treatments are at best symptomatic. These diseases are characterized by the presence of, and believed to be caused by the formation of, filamentous inclusions of α-synuclein in brain cells2,3. However, the structures of α-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that α-synuclein inclusions from the brains of individuals with MSA are made of two types of filament, each of which consists of two different protofilaments. In each type of filament, non-proteinaceous mols. are present at the interface of the two protofilaments. Using two-dimensional class averaging, we show that α-synuclein filaments from the brains of individuals with MSA differ from those of individuals with DLB, which suggests that distinct conformers or strains characterize specific synucleinopathies. As is the case with tau assemblies4-9, the structures of α-synuclein filaments extd. from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain. These findings have diagnostic and potential therapeutic relevance, esp. because of the unmet clin. need to be able to image filamentous α-synuclein inclusions in the human brain.
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Sangwan, S.; Sahay, S.; Murray, K. A.; Morgan, S.; Guenther, E. L.; Jiang, L.; Williams, C. K.; Vinters, H. V.; Goedert, M.; Eisenberg, D. S. Inhibition of Synucleinopathic Seeding by Rationally Designed Inhibitors. eLife 2020, 9, e46775 DOI: 10.7554/eLife.46775
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Inhibition of synucleinopathic seeding by rationally designed inhibitors
Sangwan, Smriti; Sahay, Shruti; Murray, Kevin A.; Morgan, Sophie; Guenther, Elizabeth L.; Jiang, Lin; Williams, Christopher K.; Vinters, Harry V.; Goedert, Michel; Eisenberg, David S.
eLife (2020), 9 (), e46775CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
Seeding, in the context of amyloid disease, is the sequential transfer of pathogenic protein aggregates from cell-to-cell within affected tissues. The structure of pathogenic seeds provides the mol. basis and enables rapid conversion of sol. protein into fibrils. To date, there are no inhibitors that specifically target seeding of Parkinson's disease (PD)-assocd. asynuclein (a-syn) fibrils, in part, due to lack of information of the structural properties of pathol. seeds. Here we design small peptidic inhibitors based on the at. structure of the core of a-syn fibrils. The inhibitors prevent a-syn aggregation in vitro and in cell culture models with binding affinities of 0.5 mM to a-syn fibril seeds. The inhibitors also show efficacy in preventing seeding by human patient-derived a-syn fibrils. Our results suggest that pathogenic seeds of a-syn contain steric zippers and suggest a therapeutic approach targeted at the spread and progression that may be applicable for PD and related synucleinopathies.
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Priss, A.; Afitska, K.; Galkin, M.; Yushchenko, D. A.; Shvadchak, V. V. Rationally Designed Protein-Based Inhibitor of α-Synuclein Fibrillization in Cells. J. Med. Chem. 2021, 64, 6827– 6837, DOI: 10.1021/acs.jmedchem.1c00086
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Rationally Designed Protein-Based Inhibitor of α-Synuclein Fibrillization in Cells
Priss, Anastasiia; Afitska, Kseniia; Galkin, Maksym; Yushchenko, Dmytro A.; Shvadchak, Volodymyr V.
Journal of Medicinal Chemistry (2021), 64 (10), 6827-6837CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
Misfolding of the neuronal protein α-synuclein (αSyn) into amyloid fibrils is involved in the development of Parkinson's disease (PD), and inhibition of this process is considered to be a promising therapeutic approach. In this work, we engineered protein inhibitors that bind to fibrils with higher affinity than the monomeric αSyn. They were developed based on the recent structural data of the αSyn fibrils and were shown to prevent fibril elongation upon binding to fibril ends. These inhibitors are highly selective to the misfolded αSyn, nontoxic, and active in cytosol in small concns. The best-performing inhibitor shows IC50 ~ 10 nM in a cell-based assay, which corresponds to the ~ 1:60 molar ratio to αSyn. It can suppress the formation of αSyn aggregates in cells that can be potentially used to slow down the spreading of the pathol. aggregates from cell to cell during the course of the PD.
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Gao, L.; Wang, W.; Wang, X.; Yang, F.; Xie, L.; Shen, J.; Brimble, M. A.; Xiao, Q.; Yao, S. Q. Fluorescent Probes for Bioimaging of Potential Biomarkers in Parkinson’s Disease. Chem. Soc. Rev. 2021, 50, 1219– 1250, DOI: 10.1039/d0cs00115e
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Fluorescent probes for bioimaging of potential biomarkers in Parkinson's disease
Gao, Liqian; Wang, Wei; Wang, Xuan; Yang, Fen; Xie, Liuxing; Shen, Jun; Brimble, Margaret A.; Xiao, Qicai; Yao, Shao Q.
Chemical Society Reviews (2021), 50 (2), 1219-1250CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. Parkinson's disease (PD), as the second most common neurodegenerative disease, is caused by complex pathol. processes and currently remains very difficult to treat. PD brings great distress to patients and imposes a heavy economic burden on society. The no. of PD patients is growing as the aging population increases worldwide. Therefore, it is crucial to develop new tools for aiding the early diagnosis and treatment of PD. The significant pathol. features involved in PD include the abnormal accumulation of α-synuclein, metal ion dyshomeostasis, oxidative stress, mitochondrial dysfunction and neurotransmitter deficiencies. In recent years, fluorescent probes have emerged as a powerful bioimaging tool with potential to help understand the pathol. processes of PD via the detection and monitoring of pathol. features. In this review, we comprehensively summarize the design and working mechanisms of fluorescent probes along with their applications in the detection of various PD biomarkers. We also discuss the current limitations of fluorescent probes and provide perspectives on how these limitations can be overcome to develop better fluorescent probes suitable for application in clin. trials in the future. We hope that this review provides valuable information and guidance for the development of new fluorescent probes that can be used clin. in the early diagnosis of PD and contributes to the development of efficient PD drugs in the future.
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Ferrie, J. J.; Lengyel-Zhand, Z.; Janssen, B.; Lougee, M. G.; Giannakoulias, S.; Hsieh, C.-J.; Pagar, V. V.; Weng, C.-C.; Xu, H.; Graham, T. J. A.; Lee, V. M.-Y.; Mach, R. H.; Petersson, E. J. Identification of a Nanomolar Affinity α-Synuclein Fibril Imaging Probe by Ultra-High Throughput in Silico Screening. Chem. Sci. 2020, 11, 12746– 12754, DOI: 10.1039/d0sc02159h
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Identification of a nanomolar affinity alpha-synuclein fibril imaging probe by ultra-high throughput in silico screening
Ferrie, John J.; Lengyel-Zhand, Zsofia; Janssen, Bieneke; Lougee, Marshall G.; Giannakoulias, Sam; Hsieh, Chia-Ju; Pagar, Vinayak Vishnu; Weng, Chi-Chang; Xu, Hong; Graham, Thomas J. A.; Lee, Virginia M.-Y.; Mach, Robert H.; Petersson, E. James
Chemical Science (2020), 11 (47), 12746-12754CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
Small mols. that bind with high affinity and specificity to fibrils of the α-synuclein (αS) protein have the potential to serve as positron emission tomog. (PET) imaging probes to aid in the diagnosis of Parkinson's disease and related synucleinopathies. To identify such mols., we employed an ultra-high throughput in silico screening strategy using idealized pseudo-ligands termed exemplars to identify compds. for exptl. binding studies. For the top hit from this screen, we used photo-crosslinking to confirm its binding site and studied the structure-activity relationship of its analogs to develop multiple mols. with nanomolar affinity for αS fibrils and moderate specificity for α;S over Aβfibrils. Lastly, we demonstrated the potential of the lead analog as an imaging probe by measuring binding to αS-enriched homogenates from mouse brain tissue using a radiolabeled analog of the identified mols. This study demonstrates the validity of our powerful new approach to the discovery of PET probes for challenging mol. targets.
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Lengyel-Zhand, Z.; Ferrie, J. J.; Janssen, B.; Hsieh, C. J.; Graham, T.; Xu, K. Y.; Haney, C. M.; Lee, V. M. Y.; Trojanowski, J. Q.; Petersson, E. J.; Mach, R. H. Synthesis and Characterization of High Affinity Fluorogenic α-Synuclein Probes. Chem. Commun. 2020, 56, 3567– 3570, DOI: 10.1039/c9cc09849f
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Synthesis and characterization of high affinity fluorogenic α-synuclein probes
Lengyel-Zhand, Zsofia; Ferrie, John J.; Janssen, Bieneke; Hsieh, Chia-Ju; Graham, Thomas; Xu, Kui-ying; Haney, Conor M.; Lee, Virginia M.-Y.; Trojanowski, John Q.; Petersson, E. James; Mach, Robert H.
Chemical Communications (Cambridge, United Kingdom) (2020), 56 (24), 3567-3570CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
Fluorescent small mols. are powerful tools for imaging α-synuclein pathol. in vitro and in vivo. In this work, we explore benzofuranone as a potential scaffold for the design of fluorescent α-synuclein probes. These compds. have high affinity for α-synuclein, show fluorescent turn-on upon binding to fibrils, and display different binding to Lewy bodies, Lewy neurites and glial cytoplasmic inclusion pathologies in post-mortem brain tissue. These studies not only reveal the potential of benzofuranone compds. as α-synuclein specific fluorescent probes, but also have implications for the ways in which α-synucleinopathies are conformationally different and display distinct small mol. binding sites.
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Hsieh, C. J.; Ferrie, J. J.; Xu, K.; Lee, I.; Graham, T. J. A.; Tu, Z.; Yu, J.; Dhavale, D.; Kotzbauer, P.; Petersson, E. J.; Mach, R. H. Alpha Synuclein Fibrils Contain Multiple Binding Sites for Small Molecules. ACS Chem. Neurosci. 2018, 9, 2521– 2527, DOI: 10.1021/acschemneuro.8b00177
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Alpha Synuclein Fibrils Contain Multiple Binding Sites for Small Molecules
Hsieh, Chia-Ju; Ferrie, John J.; Xu, Kuiying; Lee, Iljung; Graham, Thomas J. A.; Tu, Zhude; Yu, Jennifer; Dhavale, Dhruva; Kotzbauer, Paul; Petersson, E. James; Mach, Robert H.
ACS Chemical Neuroscience (2018), 9 (11), 2521-2527CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
The fibrillary aggregation of the α-synuclein (Asyn) is a hallmark of Parkinson's disease, and the identification of small mol. binding sites on fibrils is essential to the development of diagnostic imaging probes. Here, a series of mol. modeling, photoaffinity labeling, mass spectrometry,, and radioligand binding studies were conducted on Asyn fibrils. The results of these studies revealed the presence of 3 different binding sites within fibrillar Asyn capable of binding small mols. with moderate to high affinity. A knowledge of the amino acid residues in these binding sites will be important in the design of high affinity probes capable of imaging fibrillary species of Asyn.
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Eberling, J. L.; Dave, K. D.; Frasier, M. A. α-Synuclein Imaging: A Critical Need for Parkinson’s Disease Research. J. Parkinson’s Dis. 2013, 3, 565– 567, DOI: 10.3233/JPD-130247
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α-synuclein Imaging: A Critical Need for Parkinson's Disease Research
Eberling, Jamie L.; Dave, Kuldip D.; Frasier, Mark A.
Journal of Parkinson's Disease (2013), 3 (4), 565-567CODEN: JPDOAP; ISSN:1877-7171. (IOS Press)
A review. The development of an α-synuclein imaging agent could be transformative for Parkinson's disease research and drug development. The ability to image α-synuclein in the brain would enable tracking of the degree and location of pathol. over time and monitoring of therapies aimed at reducing α-synuclein levels. The Michael J. Fox Foundation has assembled a consortium of researchers to develop an α-synuclein radiotracer for use in positron emission tomog. (PET) imaging studies. While this poses a no. of challenges they should not be insurmountable and lessons learned from the development of tau radiotracers should provide valuable insights.
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Kulenkampff, K.; Wolf Perez, A. M.; Sormanni, P.; Habchi, J.; Vendruscolo, M. Quantifying Misfolded Protein Oligomers as Drug Targets and Biomarkers in Alzheimer and Parkinson Diseases. Nat. Rev. Chem. 2021, 5, 277– 294, DOI: 10.1038/s41570-021-00254-9
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Quantifying misfolded protein oligomers as drug targets and biomarkers in Alzheimer and Parkinson diseases
Kulenkampff, Klara; Wolf Perez, Adriana-M.; Sormanni, Pietro; Habchi, Johnny; Vendruscolo, Michele
Nature Reviews Chemistry (2021), 5 (4), 277-294CODEN: NRCAF7; ISSN:2397-3358. (Nature Portfolio)
A review. Protein misfolding and aggregation are characteristic of a wide range of neurodegenerative disorders, including Alzheimer and Parkinson diseases. A hallmark of these diseases is the aggregation of otherwise sol. and functional proteins into amyloid aggregates. Although for many decades such amyloid deposits have been thought to be responsible for disease progression, it is now increasingly recognized that the misfolded protein oligomers formed during aggregation are, instead, the main agents causing pathol. processes. These oligomers are transient and heterogeneous, which makes it difficult to detect and quantify them, generating confusion about their exact role in disease. The lack of suitable methods to address these challenges has hampered efforts to investigate the mol. mechanisms of oligomer toxicity and to develop oligomer-based diagnostic and therapeutic tools to combat protein misfolding diseases. In this Review, we describe methods to quantify misfolded protein oligomers, with particular emphasis on diagnostic applications as disease biomarkers and on therapeutic applications as target biomarkers. The development of these methods is ongoing, and we discuss the challenges that remain to be addressed to establish measurement tools capable of overcoming existing limitations and to meet present needs.
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Fayyad, M.; Salim, S.; Majbour, N.; Erskine, D.; Stoops, E.; Mollenhauer, B.; El-Agnaf, O. M. A. Parkinson’s Disease Biomarkers Based on α-Synuclein. J. Neurochem. 2019, 150, 626– 636, DOI: 10.1111/jnc.14809
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Parkinson's disease biomarkers based on α-synuclein
Fayyad, Muneera; Salim, Safa; Majbour, Nour; Erskine, Daniel; Stoops, Erik; Mollenhauer, Brit; El-Agnaf, Omar M. A.
Journal of Neurochemistry (2019), 150 (5), 626-636CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
A review. Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease and is estd. to affect approx. 1-4% of individuals aged over 60 years old. Although considerable efforts have been invested into developing disease-modifying therapies for Parkinson's disease, such efforts have been confounded by the difficulty in accurately diagnosing Parkinson's disease during life to enable accurate patient stratification for clin. trialling of candidate therapeutics. Therefore, the search for effective biomarkers that can be accurately evaluated during life with non-invasive means is a pressing issue in the field. Since the discovery of α-synuclein (α-syn) as a protein linked to a familial form of Parkinson's disease, later identified as the major protein component of the neuropathol. hallmark of idiopathic Parkinson's disease, considerable interest has focused on this protein and its distinct conformers. We describe here the progress that has been made in the area of Parkinson's disease biomarker discovery with a focus on α-synuclein. In particular, we highlight the novel assays that have been employed and the increasing complexity in evaluating α-synuclein with regard to the considerable diversity of conformers that exist in the biofluids and peripheral tissues under disease conditions.
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Brown, J. W. P.; Buell, A. K.; Michaels, T. C. T.; Meisl, G.; Carozza, J.; Flagmeier, P.; Vendruscolo, M.; Knowles, T. P. J.; Dobson, C. M.; Galvagnion, C. β-Synuclein Suppresses Both the Initiation and Amplification Steps of α-Synuclein Aggregation via Competitive Binding to Surfaces. Sci. Rep. 2016, 6, 36010 DOI: 10.1038/srep36010
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β-Synuclein suppresses both the initiation and amplification steps of α-synuclein aggregation via competitive binding to surfaces
Brown, James W. P.; Buell, Alexander K.; Michaels, Thomas C. T.; Meisl, Georg; Carozza, Jacqueline; Flagmeier, Patrick; Vendruscolo, Michele; Knowles, Tuomas P. J.; Dobson, Christopher M.; Galvagnion, Celine
Scientific Reports (2016), 6 (), 36010CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
α-Synuclein is an intrinsically disordered protein that is assocd. with the pathogenesis of Parkinson's disease through the processes involved in the formation of amyloid fibrils. α and β-synuclein are homologous proteins found at comparable levels in presynaptic terminals but β-synuclein has a greatly reduced propensity to aggregate and indeed has been found to inhibit α-synuclein aggregation. In this paper, we describe how sequence differences between α- and β-synuclein affect individual microscopic processes in amyloid formation. In particular, we show that β-synuclein strongly suppresses both lipid-induced aggregation and secondary nucleation of α-synuclein by competing for binding sites at the surfaces of lipid vesicles and fibrils, resp. These results suggest that β-synuclein can act as a natural inhibitor of α-synuclein aggregation by reducing both the initiation of its self-assembly and the proliferation of its aggregates.
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Staats, R.; Michaels, T. C. T.; Flagmeier, P.; Chia, S.; Horne, R. I.; Habchi, J.; Linse, S.; Knowles, T. P. J.; Dobson, C. M.; Vendruscolo, M. Screening of Small Molecules Using the Inhibition of Oligomer Formation in α-Synuclein Aggregation as a Selection Parameter. Commun. Chem. 2020, 3, 191, DOI: 10.1038/s42004-020-00412-y
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Screening of small molecules using the inhibition of oligomer formation in α-synuclein aggregation as a selection parameter
Staats, Roxine; Michaels, Thomas C. T.; Flagmeier, Patrick; Chia, Sean; Horne, Robert I.; Habchi, Johnny; Linse, Sara; Knowles, Tuomas P. J.; Dobson, Christopher M.; Vendruscolo, Michele
Communications Chemistry (2020), 3 (1), 191CODEN: CCOHCT; ISSN:2399-3669. (Nature Research)
The aggregation of α-synuclein is a central event in Parkinsons disease and related synucleinopathies. Since pharmacol. targeting this process, however, has not yet resulted in approved disease-modifying treatments, there is an unmet need of developing novel methods of drug discovery. In this context, the use of chem. kinetics has recently enabled accurate quantifications of the microscopic steps leading to the proliferation of protein misfolded oligomers. As these species are highly neurotoxic, effective therapeutic strategies may be aimed at reducing their nos. Here, we exploit this quant. approach to develop a screening strategy that uses the reactive flux toward α-synuclein oligomers as a selection parameter. Using this approach, we evaluate the efficacy of a library of flavone derivs., identifying apigenin as a compd. that simultaneously delays and reduces the formation of α-synuclein oligomers. These results demonstrate a compd. selection strategy based on the inhibition of the formation of α-synuclein oligomers, which may be key in identifying small mols. in drug discovery pipelines for diseases assocd. with α-synuclein aggregation.
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Perni, M.; Flagmeier, P.; Limbocker, R.; Cascella, R.; Aprile, F. A.; Galvagnion, C.; Heller, G. T.; Meisl, G.; Chen, S. W.; Kumita, J. R.; Challa, P. K.; Kirkegaard, J. B.; Cohen, S. I. A.; Mannini, B.; Barbut, D.; Nollen, E. A. A.; Cecchi, C.; Cremades, N.; Knowles, T. P. J.; Chiti, F.; Zasloff, M.; Vendruscolo, M.; Dobson, C. M. Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine. ACS Chem. Biol. 2018, 13, 2308– 2319, DOI: 10.1021/acschembio.8b00466
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Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine
Perni, Michele; Flagmeier, Patrick; Limbocker, Ryan; Cascella, Roberta; Aprile, Francesco A.; Galvagnion, Celine; Heller, Gabriella T.; Meisl, Georg; Chen, Serene W.; Kumita, Janet R.; Challa, Pavan K.; Kirkegaard, Julius B.; Cohen, Samuel I. A.; Mannini, Benedetta; Barbut, Denise; Nollen, Ellen A. A.; Cecchi, Cristina; Cremades, Nunilo; Knowles, Tuomas P. J.; Chiti, Fabrizio; Zasloff, Michael; Vendruscolo, Michele; Dobson, Christopher M.
ACS Chemical Biology (2018), 13 (8), 2308-2319CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
The aggregation of α-synuclein, an intrinsically disordered protein that is highly abundant in neurons, is closely assocd. with the onset and progression of Parkinson's disease. We have shown previously that the aminosterol squalamine can inhibit the lipid induced initiation process in the aggregation of α-synuclein, and we report here that the related compd. trodusquemine is capable of inhibiting not only this process but also the fibril-dependent secondary pathways in the aggregation reaction. We further demonstrate that trodusquemine can effectively suppress the toxicity of α-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic redn. in the no. of α-synuclein inclusions in a Caenorhabditis elegans model of Parkinson's disease, eliminates the related muscle paralysis, and increases lifespan. On the basis of these findings, we show that trodusquemine is able to inhibit multiple events in the aggregation process of α-synuclein and hence to provide important information about the link between such events and neurodegeneration, as it is initiated and progresses. Particularly in the light of the previously reported ability of trodusquemine to cross the blood-brain barrier and to promote tissue regeneration, the present results suggest that this compd. has the potential to be an important therapeutic candidate for Parkinson's disease and related disorders.
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Pujols, J.; Peña-Díaz, S.; Pallarès, I.; Ventura, S. Chemical Chaperones as Novel Drugs for Parkinson’s Disease. Trends Mol. Med. 2020, 26, 408– 421, DOI: 10.1016/j.molmed.2020.01.005
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Chemical Chaperones as Novel Drugs for Parkinson's Disease
Pujols, Jordi; Pena-Diaz, Samuel; Pallares, Irantzu; Ventura, Salvador
Trends in Molecular Medicine (2020), 26 (4), 408-421CODEN: TMMRCY; ISSN:1471-4914. (Elsevier Ltd.)
A review. Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and the accumulation of deposits of α-synuclein (α-syn) in the brain. The pivotal role of α-syn aggregation in PD makes it an attractive target for potential disease-modifying therapies. However, the disordered nature of the protein, its multistep aggregation mechanism, and the lack of structural information on intermediate species complicate the discovery of modulators of α-syn amyloid deposition. Despite these difficulties, small mols. have been shown to block the misfolding and aggregation of α-syn, and can even disentangle mature α-syn amyloid fibrils. In this review we provide an updated overview of these leading small compds. and discuss how these chem. chaperones hold great promise to alter the course of PD progression.
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Gaspar, R.; Meisl, G.; Buell, A. K.; Young, L.; Kaminski, C. F.; Knowles, T. P. J.; Sparr, E.; Linse, S. Secondary Nucleation of Monomers on Fibril Surface Dominates α-Synuclein Aggregation and Provides Autocatalytic Amyloid Amplification. Q. Rev. Biophys. 2017, 50, e6 DOI: 10.1017/S0033583516000172
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Secondary nucleation of monomers on fibril surface dominates α-synuclein aggregation and provides autocatalytic amyloid amplification
Gaspar, Ricardo; Meisl, Georg; Buell, Alexander K.; Young, Laurence; Kaminski, Clemens F.; Knowles, Tuomas P. J.; Sparr, Emma; Linse, Sara
Quarterly Reviews of Biophysics (2017), 50 (), e6/1-e6/12CODEN: QURBAW; ISSN:0033-5835. (Cambridge University Press)
Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites contg. α-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a secondary process at mildly acidic pH, as in endosomes and other organelles. This effect manifests as a strong acceleration of the aggregation in the presence of seeds and a weak dependence of the aggregation rate on monomer concn. The mol. mechanism underlying this process could be nucleation of monomers on fibril surfaces or fibril fragmentation. Here, we aim to distinguish between these mechanisms. The nature of the secondary processes was investigated using differential sedimentation anal., trap and seed expts., quartz crystal microbalance expts. and super-resoln. microscopy. The results identify secondary nucleation of monomers on the fibril surface as the dominant secondary process leading to rapid generation of new aggregates, while no significant contribution from fragmentation was found. The newly generated oligomeric species quickly elongate to further serve as templates for secondary nucleation and this may have important implications in the spreading of PD.
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Michaels, T. C. T.; Lazell, H. W.; Arosio, P.; Knowles, T. P. J. Dynamics of Protein Aggregation and Oligomer Formation Governed by Secondary Nucleation. J. Chem. Phys. 2015, 143, 054901 DOI: 10.1063/1.4927655
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Dynamics of protein aggregation and oligomer formation governed by secondary nucleation
Michaels, Thomas C. T.; Lazell, Hamish W.; Arosio, Paolo; Knowles, Tuomas P. J.
Journal of Chemical Physics (2015), 143 (5), 054901/1-054901/15CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
The formation of aggregates in many protein systems can be significantly accelerated by secondary nucleation, a process where existing assemblies catalyze the nucleation of new species. In particular, secondary nucleation has emerged as a central process controlling the proliferation of many filamentous protein structures, including mol. species related to diseases such as sickle cell anemia and a range of neurodegenerative conditions. Increasing evidence suggests that the phys. size of protein filaments plays a key role in detg. their potential for deleterious interactions with living cells, with smaller aggregates of misfolded proteins, oligomers, being particularly toxic. It is thus crucial to progress towards an understanding of the factors that control the sizes of protein aggregates. However, the influence of secondary nucleation on the time evolution of aggregate size distributions has been challenging to quantify. This difficulty originates in large part from the fact that secondary nucleation couples the dynamics of species distant in size space. Here, we approach this problem by presenting an anal. treatment of the master equation describing the growth kinetics of linear protein structures proliferating through secondary nucleation and provide closed-form expressions for the temporal evolution of the resulting aggregate size distribution. We show how the availability of anal. solns. for the full filament distribution allows us to identify the key phys. parameters that control the sizes of growing protein filaments. Furthermore, we use these results to probe the dynamics of the populations of small oligomeric species as they are formed through secondary nucleation and discuss the implications of our work for understanding the factors that promote or curtail the prodn. of these species with a potentially high deleterious biol. activity. (c) 2015 American Institute of Physics.
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Chia, S.; Habchi, J.; Michaels, T. C. T.; Cohen, S. I. A.; Linse, S.; Dobson, C. M.; Knowles, T. P. J.; Vendruscolo, M. SAR by Kinetics for Drug Discovery in Protein Misfolding Diseases. Proc. Natl. Acad. Sci. U.S.A. 2018, 115, 10245– 10250, DOI: 10.1073/pnas.1807884115
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SAR by kinetics for drug discovery in protein misfolding diseases
Chia, Sean; Habchi, Johnny; Michaels, Thomas C. T.; Cohen, Samuel I. A.; Linse, Sara; Dobson, Christopher M.; Knowles, Tuomas P. J.; Vendruscolo, Michele
Proceedings of the National Academy of Sciences of the United States of America (2018), 115 (41), 10245-10250CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compds. that inhibit the formation of protein oligomers. To achieve this goal, the authors report a structure-activity relation (SAR) approach based on chem. kinetics to est. quant. how small mols. modify the reactive flux toward oligomers. The authors use this est. to derive chem. rules in the case of the amyloid beta peptide (Aβ), which the authors then exploit to optimize starting compds. to curtail Aβ oligomer formation. The authors demonstrate this approach by converting an inactive rhodanine compd. into an effective inhibitor of Aβ oligomer formation by generating chem. derivs. in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the prodn. of protein oligomers.
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Le Guilloux, V.; Schmidtke, P.; Tuffery, P. Fpocket: An Open Source Platform for Ligand Pocket Detection. BMC Bioinf. 2009, 10, S6 DOI: 10.1186/1471-2105-10-168
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Buell, A. K.; Galvagnion, C.; Gaspar, R.; Sparr, E.; Vendruscolo, M.; Knowles, T. P. J.; Linse, S.; Dobson, C. M. Solution Conditions Determine the Relative Importance of Nucleation and Growth Processes in α-Synuclein Aggregation. Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 7671– 7676, DOI: 10.1073/pnas.1315346111
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Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation
Buell, Alexander K.; Galvagnion, Celine; Gaspar, Ricardo; Sparr, Emma; Vendruscolo, Michele; Knowles, Tuomas P. J.; Linse, Sara; Dobson, Christopher M.
Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (21), 7671-7676CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
The formation of amyloid fibrils by the intrinsically disordered protein α-synuclein is a hallmark of Parkinson's disease (PD). To characterize the microscopic steps in the mechanism of aggregation of this protein, the authors used in vitro aggregation assays in the presence of preformed seed fibrils to det. the mol. rate const. of fibril elongation under a range of different conditions. The authors showed that α-synuclein amyloid fibrils grew by monomer and not oligomer addn. and were subject to higher-order assembly processes that decreased their capacity to grow. The authors also found that at neutral pH under quiescent conditions homogeneous primary nucleation and secondary processes, such as fragmentation and surface-assisted nucleation, which can lead to proliferation of the total no. of aggregates, were undetectable. At pH values of <6, however, the rate of secondary nucleation increased dramatically, leading to a completely different balance between the nucleation and growth of aggregates. Thus, at mildly acidic pH values, such as those, e.g., that are present in some intracellular locations, including endosomes and lysosomes, multiplication of aggregates was much faster than at normal physiol. pH values, largely as a consequence of much more rapid secondary nucleation. These findings provide new insights into possible mechanisms of α-synuclein aggregation and aggregate spreading in the context of PD.
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Sterling, T.; Irwin, J. J. ZINC 15 - Ligand Discovery for Everyone. J. Chem. Inf. Model. 2015, 55, 2324– 2337, DOI: 10.1021/acs.jcim.5b00559
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ZINC 15 - Ligand Discovery for Everyone
Sterling, Teague; Irwin, John J.
Journal of Chemical Information and Modeling (2015), 55 (11), 2324-2337CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
Many questions about the biol. activity and availability of small mols. remain inaccessible to investigators who could most benefit from their answers. To narrow the gap between chemoinformatics and biol., we have developed a suite of ligand annotation, purchasability, target, and biol. assocn. tools, incorporated into ZINC and meant for investigators who are not computer specialists. The new version contains over 120 million purchasable "drug-like" compds. - effectively all org. mols. that are for sale - a quarter of which are available for immediate delivery. ZINC connects purchasable compds. to high-value ones such as metabolites, drugs, natural products, and annotated compds. from the literature. Compds. may be accessed by the genes for which they are annotated as well as the major and minor target classes to which those genes belong. It offers new anal. tools that are easy for nonspecialists yet with few limitations for experts. ZINC retains its original 3D roots - all mols. are available in biol. relevant, ready-to-dock formats. ZINC is freely available at http://zinc15.docking.org.
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Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach to Enable Alignment of Druglike Properties. ACS Chem. Neurosci. 2010, 1, 435– 449, DOI: 10.1021/cn100008c
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Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties
Wager, Travis T.; Hou, Xinjun; Verhoest, Patrick R.; Villalobos, Anabella
ACS Chemical Neuroscience (2010), 1 (6), 435-449CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
The interplay among commonly used physicochem. properties in drug design was examd. and utilized to create a prospective design tool focused on the alignment of key druglike attributes. Using a set of six physicochem. parameters ((a) lipophilicity, calcd. partition coeff. (ClogP); (b) calcd. distribution coeff. at pH = 7.4 (ClogD); (c) mol. wt. (MW); (d) topol. polar surface area (TPSA); (e) no. of hydrogen bond donors (HBD); (f) most basic center (pKa)), a druglikeness central nervous system multiparameter optimization (CNS MPO) algorithm was built and applied to a set of marketed CNS drugs (N = 119) and Pfizer CNS candidates (N = 108), as well as to a large diversity set of Pfizer proprietary compds. (N = 11 303). The novel CNS MPO algorithm showed that 74% of marketed CNS drugs displayed a high CNS MPO score (MPO desirability score ≥ 4, using a scale of 0-6), in comparison to 60% of the Pfizer CNS candidates. This anal. suggests that this algorithm could potentially be used to identify compds. with a higher probability of successfully testing hypotheses in the clinic. In addn., a relationship between an increasing CNS MPO score and alignment of key in vitro attributes of drug discovery (favorable permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and safety) was seen in the marketed CNS drug set, the Pfizer candidate set, and the Pfizer proprietary diversity set. The CNS MPO scoring function offers advantages over hard cutoffs or utilization of single parameters to optimize structure-activity relationships (SAR) by expanding medicinal chem. design space through a holistic assessment approach. Based on six physicochem. properties commonly used by medicinal chemists, the CNS MPO function may be used prospectively at the design stage to accelerate the identification of compds. with increased probability of success.
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Trott, O.; Olson, A. J. AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading. J. Comput. Chem. 2009, 31, 455– 461, DOI: 10.1002/jcc.21334
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Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. J. Med. Chem. 2004, 47, 1739– 1749, DOI: 10.1021/jm0306430
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Glide: A new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy
Friesner, Richard A.; Banks, Jay L.; Murphy, Robert B.; Halgren, Thomas A.; Klicic, Jasna J.; Mainz, Daniel T.; Repasky, Matthew P.; Knoll, Eric H.; Shelley, Mee; Perry, Jason K.; Shaw, David E.; Francis, Perry; Shenkin, Peter S.
Journal of Medicinal Chemistry (2004), 47 (7), 1739-1749CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
A review. Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystd. PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 Å in nearly half of the cases and are greater than 2 Å in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
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Butina, D. Unsupervised Data Base Clustering Based on Daylight’s Fingerprint and Tanimoto Similarity: A Fast and Automated Way to Cluster Small and Large Data Sets. J. Chem. Inf. Comput. Sci. 1999, 39, 747– 750, DOI: 10.1021/ci9803381
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Unsupervised data base clustering based on Daylight's fingerprint and Tanimoto similarity: a fast and automated way to cluster small and large data sets
Butina, Darko
Journal of Chemical Information and Computer Sciences (1999), 39 (4), 747-750CODEN: JCISD8; ISSN:0095-2338. (American Chemical Society)
Jarvis-Patrick's (J-P) algorithm is one of the most commonly used clustering algorithms within the global pharmaceutical industry. The implementation of the J-P under Daylight software, using Daylight's fingerprints and the Tanimoto similarity index, can deal with sets of 100 k mols. in a matter of a few hours. However, the J-P clustering algorithm has several assocd. problems which make it difficult to cluster large data sets in a consistent and timely manner. The clusters produced are greatly dependent on the choice of the two parameters needed to run J-P clustering, such that this method tends to produce clusters which are either very large and heterogeneous or homogeneous but too small. In any case, J-P always requires time-consuming manual tuning. An algorithm which will identify dense clusters where similarity within each cluster reflects the Tanimoto value used for the clustering and, more importantly, where the cluster centroid will be at least similar, at the given Tanimoto value, to every other mol. within the cluster in a consistent and automated manner, is presented. The similarity term used throughout the paper reflects the overall similarity between two given mols., as defined by Daylight's fingerprints and the Tanimoto similarity index.
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Flagmeier, P.; Meisl, G.; Vendruscolo, M.; Knowles, T. P. J.; Dobson, C. M.; Buell, A. K.; Galvagnion, C. Mutations Associated with Familial Parkinson’s Disease Alter the Initiation and Amplification Steps of α-Synuclein Amyloid Formation. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 10328– 10333, DOI: 10.1073/pnas.1604645113
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Mutations associated with familial Parkinson's disease alter the initiation and amplification steps of α-synuclein aggregation
Flagmeier, Patrick; Meisl, Georg; Vendruscolo, Michele; Knowles, Tuomas P. J.; Dobson, Christopher M.; Buell, Alexander K.; Galvagnion, Celine
Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (37), 10328-10333CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Parkinson's disease is a highly debilitating neurodegenerative condition whose pathol. hallmark is the presence in nerve cells of proteinaceous deposits, known as Lewy bodies, composed primarily of amyloid fibrils of α-synuclein. Several missense mutations in the gene encoding α-synuclein have been assocd. with familial variants of Parkinson's disease and have been shown to affect the kinetics of the aggregation of the protein. Using a combination of exptl. and theor. approaches, we present a systematic in vitro study of the influence of disease-assocd. single-point mutations on the individual processes involved in α-synuclein aggregation into amyloid fibrils. We find that lipid-induced fibril prodn. and surface catalyzed fibril amplification are the processes most strongly affected by these mutations and show that familial mutations can induce dramatic changes in the crucial processes thought to be assocd. with the initiation and spreading of the aggregation of α-synuclein.
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Galvagnion, C.; Buell, A. K.; Meisl, G.; Michaels, T. C. T.; Vendruscolo, M.; Knowles, T. P. J.; Dobson, C. M. Lipid Vesicles Trigger α-Synuclein Aggregation by Stimulating Primary Nucleation. Nat. Chem. Biol. 2015, 11, 229– 234, DOI: 10.1038/nchembio.1750
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Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation
Galvagnion, Celine; Buell, Alexander K.; Meisl, Georg; Michaels, Thomas C. T.; Vendruscolo, Michele; Knowles, Tuomas P. J.; Dobson, Christopher M.
Nature Chemical Biology (2015), 11 (3), 229-234CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
α-Synuclein (α-syn) is a 140-residue intrinsically disordered protein that is involved in neuronal and synaptic vesicle plasticity, but its aggregation to form amyloid fibrils is the hallmark of Parkinson's disease (PD). The interaction between α-syn and lipid surfaces is believed to be a key feature for mediation of its normal function, but under other circumstances it is able to modulate amyloid fibril formation. Using a combination of exptl. and theor. approaches, we identify the mechanism through which facile aggregation of α-syn is induced under conditions where it binds a lipid bilayer, and we show that the rate of primary nucleation can be enhanced by three orders of magnitude or more under such conditions. These results reveal the key role that membrane interactions can have in triggering conversion of α-syn from its sol. state to the aggregated state that is assocd. with neurodegeneration and to its assocd. disease states.
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Michaels, T. C. T.; Cohen, S. I. A.; Vendruscolo, M.; Dobson, C. M.; Knowles, T. P. J. Hamiltonian Dynamics of Protein Filament Formation. Phys. Rev. Lett. 2016, 116, 038101, DOI: 10.1103/PhysRevLett.116.038101
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Hamiltonian dynamics of protein filament formation
Michaels, Thomas C. T.; Cohen, Samuel I. A.; Vendruscolo, Michele; Dobson, Christopher M.; Knowles, Tuomas P. J.
Physical Review Letters (2016), 116 (3), 038101/1-038101/6CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)
We establish the Hamiltonian structure of the rate equations describing the formation of protein filaments. We then show that this formalism provides a unified view of the behavior of a range of biol. self-assembling systems as diverse as actin. prions. and amyloidogenic polypeptides. We further demonstrate that the time-translation symmetry of the resulting Hamiltonian leads to previously unsuggested conservation laws that connect the no. and mass concns. of fibrils and allow linear growth phenomena to be equated with autocatalytic growth processes. We finally show how these results reveal simple rate laws that provide the basis for interpreting exptl. data in terms of specific mechanisms controlling the proliferation of fibrils.
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Palacio-Rodríguez, K.; Lans, I.; Cavasotto, C. N.; Cossio, P. Exponential Consensus Ranking Improves the Outcome in Docking and Receptor Ensemble Docking. Sci. Rep. 2019, 9, 5142 DOI: 10.1038/s41598-019-41594-3
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Exponential consensus ranking improves the outcome in docking and receptor ensemble docking
Palacio-Rodriguez Karen; Lans Isaias; Cossio Pilar; Cavasotto Claudio N; Cavasotto Claudio N; Cavasotto Claudio N; Cossio Pilar
Scientific reports (2019), 9 (1), 5142 ISSN:.
Consensus-scoring methods are commonly used with molecular docking in virtual screening campaigns to filter potential ligands for a protein target. Traditional consensus methods combine results from different docking programs by averaging the score or rank of each molecule obtained from individual programs. Unfortunately, these methods fail if one of the docking programs has poor performance, which is likely to occur due to training-set dependencies and scoring-function parameterization. In this work, we introduce a novel consensus method that overcomes these limitations. We combine the results from individual docking programs using a sum of exponential distributions as a function of the molecule rank for each program. We test the method over several benchmark systems using individual and ensembles of target structures from diverse protein families with challenging decoy/ligand datasets. The results demonstrate that the novel method outperforms the best traditional consensus strategies over a wide range of systems. Moreover, because the novel method is based on the rank rather than the score, it is independent of the score units, scales and offsets, which can hinder the combination of results from different structures or programs. Our method is simple and robust, providing a theoretical basis not only for molecular docking but also for any consensus strategy in general.
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Wilhelm, B. G.; Mandad, S.; Truckenbrodt, S.; Kröhnert, K.; Schäfer, C.; Rammner, B.; Koo, S. J.; Claßen, Ga.; Krauss, M.; Haucke, V.; Urlaub, H.; Rizzoli, S. O. Composition of Isolated Synaptic Boutons Reveals the Amounts of Vesicle Trafficking Proteins. Science 2014, 344, 1023– 1028, DOI: 10.1126/science.1252884
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Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins
Wilhelm, Benjamin G.; Mandad, Sunit; Truckenbrodt, Sven; Kroehnert, Katharina; Schaefer, Christina; Rammner, Burkhard; Koo, Seong Joo; Classen, Gala A.; Krauss, Michael; Haucke, Volker; Urlaub, Henning; Rizzoli, Silvio O.
Science (Washington, DC, United States) (2014), 344 (6187), 1023-1028CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
Synaptic vesicle recycling has long served as a model for the general mechanisms of cellular trafficking. We used an integrative approach, combining quant. immunoblotting and mass spectrometry to det. protein nos.; electron microscopy to measure organelle nos., sizes, and positions; and super-resoln. fluorescence microscopy to localize the proteins. Using these data, we generated a three-dimensional model of an "av." synapse, displaying 300,000 proteins in at. detail. The copy nos. of proteins involved in the same step of synaptic vesicle recycling correlated closely. In contrast, copy nos. varied over more than three orders of magnitude between steps, from about 150 copies for the endosomal fusion proteins to more than 20,000 for the exocytotic ones.
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Yang, Y.; Shi, Y.; Schweighauser, M.; Zhang, X.; Kotecha, A.; Murzin, A. G.; Garringer, H. J.; Cullinane, P. W.; Saito, Y.; Foroud, T.; Warner, T. T.; Hasegawa, K.; Vidal, R.; Murayama, S.; Revesz, T.; Ghetti, B.; Hasegawa, M.; Lashley, T.; Scheres, S. H. W.; Goedert, M. Structures of α-synuclein filaments from human brains with Lewy pathology, Nature 2022. 610 791 795 DOI: 10.1101/2022.07.12.499706610 .
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Structures of alpha synuclein filaments from human brains with Lewy pathology
Yang, Yang; Shi, Yang; Schweighauser, Manuel; Zhang, Xianjun; Kotecha, Abhay; Murzin, Alexey G.; Garringer, Holly J.; Cullinane, Patrick W.; Saito, Yuko; Foroud, Tatiana; Warner, Thomas T.; Hasegawa, Kazuko; Vidal, Ruben; Murayama, Shigeo; Revesz, Tamas; Ghetti, Bernardino; Hasegawa, Masato; Lashley, Tammaryn; Scheres, Sjors H. W.; Goedert, Michel
Nature (London, United Kingdom) (2022), 610 (7933), 791-795CODEN: NATUAS; ISSN:1476-4687. (Nature Portfolio)
Parkinson disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms. Neuropathol. it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra. PD is increasingly recognized as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis. PD dementia (PDD) is clin. and neuropathol. similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, esp. oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extd. from the brains of individuals with MSA6. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct mol. conformers of assembled α-synuclein in neurodegenerative disease.
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Cohen, S. I. A.; Arosio, P.; Presto, J.; Kurudenkandy, F. R.; Biverstål, H.; Dolfe, L.; Dunning, C.; Yang, X.; Frohm, B.; Vendruscolo, M.; Johansson, J.; Dobson, C. M.; Fisahn, A.; Knowles, T. P. J.; Linse, S. A Molecular Chaperone Breaks the Catalytic Cycle That Generates Toxic Aβ Oligomers. Nat. Struct. Mol. Biol. 2015, 22, 207– 213, DOI: 10.1038/nsmb.2971
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A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers
Cohen, Samuel I. A.; Arosio, Paolo; Presto, Jenny; Kurudenkandy, Firoz Roshan; Biverstal, Henrik; Dolfe, Lisa; Dunning, Christopher; Yang, Xiaoting; Frohm, Birgitta; Vendruscolo, Michele; Johansson, Jan; Dobson, Christopher M.; Fisahn, Andre; Knowles, Tuomas P. J.; Linse, Sara
Nature Structural & Molecular Biology (2015), 22 (3), 207-213CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been assocd. with aggregation of the amyloid-β peptide (Aβ42). Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a mol. chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiol. expts. These results reveal that mol. chaperones can help maintain protein homeostasis by selectively suppressing crit. microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.
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Perni, M.; Galvagnion, C.; Maltsev, A.; Meisl, G.; Müller, M. B. D.; Challa, P. K.; Kirkegaard, J. B.; Cohen, S. I. A.; Cascella, R.; Chen, S. W.; Limboker, R.; Sormanni, P.; Heller, G. T.; Francesco, A.; Cremades, N.; Cecchi, C.; Chiti, F.; Ellen, A. A.; Knowles, T. P. J.; Vendruscolo, M.; Bax, A.; Zasloff, M.; Dobson, C. M.; Perni, M.; Galvagnion, C.; Maltsev, A.; Meisl, G.; Müller, M. B. D.; Challa, P. K.; Julius, B.; Flagmeier, P.; Cohen, S. I. A.; Chen, S. W.; Limbocker, R.; Sormanni, P.; Heller, G. T.; Aprile, F. A.; Cremades, N.; Cecchi, C.; Chiti, F.; Nollen, E. A. A.; Tuomas, P. J.; Vendruscolo, M.; Bax, A.; Dobson, C. M.; Perni, M.; Galvagnion, C.; Maltsev, A.; Meisl, G.; Müller, M. B. D.; Challa, P. K. A Natural Product Inhibits the Initiation of α-Synuclein Aggregation and Suppresses Its Toxicity. Proc. Natl. Acad. Sci. U.S.A. 2017, 114, E1009– E1017, DOI: 10.1073/pnas.1610586114
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A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity
Perni, Michele; Galvagnion, Celine; Maltsev, Alexander; Meisl, Georg; Muller, Martin B. D.; Challa, Pavan K.; Kirkegaard, Julius B.; Flagmeier, Patrick; Cohen, Samuel I. A.; Cascella, Roberta; Chen, Serene W.; Limboker, Ryan; Sormanni, Pietro; Heller, Gabriella T.; Aprile, Francesco A.; Cremades, Nunilo; Cecchi, Cristina; Chiti, Fabrizio; Nollen, Ellen A. A.; Knowles, Tuomas P. J.; Vendruscolo, Michele; Bax, Adriaan; Zasloff, Michael; Dobson, Christopher M.
Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (6), E1009-E1017CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
The self-assembly of α-synuclein is closely assocd. with Parkinson's disease and related syndromes. The authors show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. The authors elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compd. displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. The authors also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. The authors further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic redn. of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson's disease and related conditions.
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Agerschou, E. D.; Flagmeier, P.; Saridaki, T.; Galvagnion, C.; Komnig, D.; Heid, L.; Prasad, V.; Shaykhalishahi, H.; Willbold, D.; Dobson, C. M.; Voigt, A.; Falkenburger, B.; Hoyer, W.; Buell, A. K. An Engineered Monomer Binding-Protein for α-Synuclein Efficiently Inhibits the Proliferation of Amyloid Fibrils. eLife 2019, 8, e46112 DOI: 10.7554/eLife.46112
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An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils
Agerschou, Emil Dandanell; Flagmeier, Patrick; Saridaki, Theodora; Galvagnion, Celine; Komnig, Daniel; Heid, Laetitia; Prasad, Vibha; Shaykhalishahi, Hamed; Willbold, Dieter; Dobson, Christopher M.; Voigt, Aaron; Falkenburger, Bjoern; Hoyer, Wolfgang; Buell, Alexander K.
eLife (2019), 8 (), e46112/1-e46112/31CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
Removing or preventing the formation of α-synuclein aggregates is a plausible strategy against Parkinson's disease. To this end, we have engineered the β-wrapin AS69 to bind monomeric α-synuclein with high affinity. In cultured cells, AS69 reduced the self-interaction of α-synuclein and formation of visible α-synuclein aggregates. In flies, AS69 reduced α-synuclein aggregates and the locomotor deficit resulting from α-synuclein expression in neuronal cells. In biophys. expts. in vitro, AS69 highly sub-stoichiometrically inhibited both primary and autocatalytic secondary nucleation processes, even in the presence of a large excess of monomer. We present evidence that the AS69-α-synuclein complex, rather than the free AS69, is the inhibitory species responsible for sub-stoichiometric inhibition of secondary nucleation. These results represent a new paradigm that high affinity monomer binders can lead to strongly substoichiometric inhibition of nucleation processes.
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Linse, S.; Scheidt, T.; Bernfur, K.; Vendruscolo, M.; Dobson, C. M.; Cohen, S. I. A.; Sileikis, E.; Lundqvist, M.; Qian, F.; O’Malley, T.; Bussiere, T.; Weinreb, P. H.; Xu, C. K.; Meisl, G.; Devenish, S. R. A.; Knowles, T. P. J.; Hansson, O. Kinetic Fingerprints Differentiate the Mechanisms of Action of Anti-Aβ Antibodies. Nat. Struct. Mol. Biol. 2020, 27, 1125– 1133, DOI: 10.1038/s41594-020-0505-6
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Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies
Linse, Sara; Scheidt, Tom; Bernfur, Katja; Vendruscolo, Michele; Dobson, Christopher M.; Cohen, Samuel I. A.; Sileikis, Eimantas; Lundqvist, Martin; Qian, Fang; O'Malley, Tiernan; Bussiere, Thierry; Weinreb, Paul H.; Xu, Catherine K.; Meisl, Georg; Devenish, Sean R. A.; Knowles, Tuomas P. J.; Hansson, Oskar
Nature Structural & Molecular Biology (2020), 27 (12), 1125-1133CODEN: NSMBCU; ISSN:1545-9993. (Nature Research)
The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer's disease, has driven many therapeutic efforts for the past 20 years. Failures of clin. trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irresp. of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quant. binding measurements to address the mechanism of action of four clin. stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the prodn. of oligomeric aggregates and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ. Our results reveal that, uniquely among these four antibodies, aducanumab dramatically reduces the flux of Aβ oligomers.
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Robert I. Horne, Mhd Hussein Murtada, Donghui Huo, Z. Faidon Brotzakis, Rebecca C. Gregory, Andrea Possenti, Sean Chia, Michele Vendruscolo. Exploration and Exploitation Approaches Based on Generative Machine Learning to Identify Potent Small Molecule Inhibitors of α-Synuclein Secondary Nucleation. Journal of Chemical Theory and Computation 2023, 19 (14) , 4701-4710. https://doi.org/10.1021/acs.jctc.2c01303
Robert I. Horne, Sarah E. Sandler, Michele Vendruscolo, Ulrich F. Keyser. Detection of protein oligomers with nanopores . Nature Reviews Chemistry 2025, 72 https://doi.org/10.1038/s41570-025-00694-7
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Molecular Pharmaceutics

Cite this: Mol. Pharmaceutics 2023, 20, 1, 183–193

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https://doi.org/10.1021/acs.molpharmaceut.2c00548

Published November 14, 2022

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Abstract
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Figure 1
Figure 1. Combined structure-based and kinetic-based approach to identify small molecules that bind α-synuclein fibrils and inhibit its aggregation. In the first step, computational docking is performed on a large library of small molecules. The top candidates are then clustered to identify a subset of chemically diverse compounds that exhibit high predicted binding scores for α-synuclein fibrils. Subsequently, these compounds are experimentally validated through a kinetic assay for their ability to inhibit the secondary nucleation aggregation of α-synuclein by binding to the surface of fibrils. Further rate constant analysis and fibril-binding experiments allow for the positive compounds to be characterized based on both their inhibition of the kinetic assay, as well as their binding affinity toward α-synuclein fibrils.
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Figure 2
Figure 2. Five compounds selected from the docking library inhibit the aggregation of α-synuclein. (A) Kinetic profiles of a 10 μM solution of α-synuclein in the presence of 25 nM seeds at pH 4.8 and 37 °C, in the presence of 1% DMSO alone (beige), in the presence of 10 molar equivalents of compounds A–E (represented in different colors), or in the presence of 10 molar equivalents of other compounds in the docking library that did not affect significantly α-synuclein aggregation (black). (B) Relative t_1/2 of the aggregation of α-synuclein in the presence of compounds A–E as shown in (A), normalized to the DMSO control. (C) Chemical structures of compounds A–E. Throughout, error bars represent mean ± SEM of two replicates.
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Figure 3
Figure 3. Computational docking of compounds to α-synuclein fibrils. (A–E) Binding poses of compounds A–E to the selected binding pocket in α-synuclein fibrils (centered between residues His50 and Glu57), determined either through FRED or AutoDock Vina. (F) Representation of possible binding pockets in the fibril structure (PDB: 6cu7, cyan) identified by Fpocket, with pockets in the fibril core (blue spheres), and at the fibril surface (red spheres). Key binding site residues His50 and Glu57 are shown in licorice representation.
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Figure 4
Figure 4. Compounds identified by docking specifically inhibit the proliferation of α-synuclein aggregates by secondary nucleation. (A) Kinetic profiles of a 10 μM solution of α-synuclein in the presence of 25 nM seeds at pH 4.8, 37 °C, in the presence of either 1% DMSO alone (purple) or increasing molar equivalents of compound C (represented in different colors). (B) Relative rate of fibril amplification of α-synuclein in the presence of compounds A–E as shown in (A) and Figure S3, normalized to the DMSO control. (C) Kinetic profiles of a 10 μM solution of α-synuclein in the presence of 5 μM seeds at pH 4.8, 37 °C, in the presence of either 1% DMSO alone (purple) or increasing molar equivalents of compound C (represented in different colors). Dotted lines indicate the v_max of the reaction which is used to extract the elongation rate of the aggregation process. (D) Relative rate of fibril elongation of α-synuclein in the presence of compounds A–E as shown in (C) and Figure S5,6, normalized to the DMSO control. Throughout, error bars represent mean ± SEM of three replicates.
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Figure 5
Figure 5. Compound C inhibits the reactive flux toward α-synuclein oligomers and displays binding affinity and specificity toward α-synuclein fibrils. (A) Time dependence of the reactive flux toward α-synuclein oligomers either in the presence of 1% DMSO alone (purple) or in the presence of increasing molar equivalents of compound C (represented in different colors), normalized to the DMSO control. (B) Change in fluorescence polarization (in mP units) of 10 μM compound C with increasing concentrations of either α-synuclein fibrils (purple) or Aβ42 fibrils (red). The solid lines are fits to the points using a one-step binding curve, estimating a K_d of 4 μM for compound C toward α-synuclein fibrils. (C) Total ion current (TIC) of 10 μM compound C bound and unbound to 10 μM α-synuclein fibrils detected by mass spectrometry (see the Materials and Methods section). (D) Representative images indicating either the fluorescence of the red channel (amyloid-specific dye pFTAA) or the green channel (compound C) following incubation in the absence (top) or presence (bottom) of 100 nM α-synuclein fibrils. Throughout, error bars represent mean ± SEM of two replicates.
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  α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies
  Prots, Iryna; Grosch, Janina; Brazdis, Razvan-Marius; Simmnacher, Katrin; Veber, Vanesa; Havlicek, Steven; Hannappel, Christian; Krach, Florian; Krumbiegel, Mandy; Schuetz, Oliver; Reis, Andre; Wrasidlo, Wolfgang; Galasko, Douglas R.; Groemer, Teja W.; Masliah, Eliezer; Schloetzer-Schrehardt, Ursula; Xiang, Wei; Winkler, Juergen; Winner, Beate
  Proceedings of the National Academy of Sciences of the United States of America (2018), 115 (30), 7813-7818CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  α-Synuclein (α-Syn) aggregation, proceeding from oligomers to fibrils, is one central hallmark of neurodegeneration in synucleinopathies. α-Syn oligomers are toxic by triggering neurodegenerative processes in in vitro and in vivo models. However, the precise contribution of α-Syn oligomers to neurite pathol. in human neurons and the underlying mechanisms remain unclear. Here, we demonstrate the formation of oligomeric α-Syn intermediates and reduced axonal mitochondrial transport in human neurons derived from induced pluripotent stem cells (iPSC) from a Parkinson's disease patient carrying an α-Syn gene duplication. We further show that increased levels of α-Syn oligomers disrupt axonal integrity in human neurons. We apply an α-Syn oligomerization model by expressing α-Syn oligomer-forming mutants (E46K and E57K) and wild-type α-Syn in human iPSC-derived neurons. Pronounced α-Syn oligomerization led to impaired anterograde axonal transport of mitochondria, which can be restored by the inhibition of α-Syn oligomer formation. Furthermore, α-Syn oligomers were assocd. with a subcellular relocation of transport-regulating proteins Miro1, KLC1, and Tau as well as reduced ATP levels, underlying axonal transport deficits. Consequently, reduced axonal d. and structural synaptic degeneration were obsd. in human neurons in the presence of high levels of α-Syn oligomers. Together, increased dosage of α-Syn resulting in α-Syn oligomerization causes axonal transport disruption and energy deficits, leading to synapse loss in human neurons. This study identifies α-Syn oligomers as the crit. species triggering early axonal dysfunction in synucleinopathies.
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11. 11
  Ludtmann, M. H. R.; Angelova, P. R.; Horrocks, M. H.; Choi, M. L.; Rodrigues, M.; Baev, A. Y.; Berezhnov, A. V.; Yao, Z.; Little, D.; Banushi, B.; Al-Menhali, A. S.; Ranasinghe, R. T.; Whiten, D. R.; Yapom, R.; Dolt, K. S.; Devine, M. J.; Gissen, P.; Kunath, T.; Jaganjac, M.; Pavlov, E. V.; Klenerman, D.; Abramov, A. Y.; Gandhi, S. α-Synuclein Oligomers Interact with ATP Synthase and Open the Permeability Transition Pore in Parkinson’s Disease. Nat. Commun. 2018, 9, 2293 DOI: 10.1038/s41467-018-04422-2
  11
  α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease
  Ludtmann Marthe H R; Angelova Plamena R; Abramov Andrey Y; Ludtmann Marthe H R; Horrocks Mathew H; Rodrigues Margarida; Ranasinghe Rohan T; Whiten Daniel R; Klenerman David; Horrocks Mathew H; Horrocks Mathew H; Choi Minee L; Yao Zhi; Gandhi Sonia; Choi Minee L; Yao Zhi; Gandhi Sonia; Baev Artyom Y; Berezhnov Alexey V; Little Daniel; Banushi Blerida; Devine Michael J; Gissen Paul; Al-Menhali Afnan Saleh; Jaganjac Morana; Yapom Ratsuda; Dolt Karamjit Singh; Kunath Tilo; Devine Michael J; Pavlov Evgeny V; Klenerman David
  Nature communications (2018), 9 (1), 2293 ISSN:.
  Protein aggregation causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric α-synuclein improves ATP synthase efficiency. Here, we report that aggregation of monomers generates beta sheet-rich oligomers that localise to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric α-synuclein impairs complex I-dependent respiration. Oligomers induce selective oxidation of the ATP synthase beta subunit and mitochondrial lipid peroxidation. These oxidation events increase the probability of permeability transition pore (PTP) opening, triggering mitochondrial swelling, and ultimately cell death. Notably, inhibition of oligomer-induced oxidation prevents the pathological induction of PTP. Inducible pluripotent stem cells (iPSC)-derived neurons bearing SNCA triplication, generate α-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of α-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson's disease.
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12. 12
  Hughes, C. D.; Choi, M. L.; Ryten, M.; Hopkins, L.; Drews, A.; Botía, J. A.; Iljina, M.; Rodrigues, M.; Gagliano, S. A.; Gandhi, S.; Klenerman, D.; Bryant, C. Picomolar Concentrations of Oligomeric Alpha - Synuclein Sensitizes TLR4 to Play an Initiating Role in Parkinson’ s Disease Pathogenesis. Acta Neuropathol. 2019, 137, 103– 120, DOI: 10.1007/s00401-018-1907-y
  12
  Picomolar concentrations of oligomeric alpha-synuclein sensitizes TLR4 to play an initiating role in Parkinson's disease pathogenesis
  Hughes, Craig D.; Choi, Minee L.; Ryten, Mina; Hopkins, Lee; Drews, Anna; Botia, Juan A.; Iljina, Maria; Rodrigues, Magarida; Gagliano, Sarah A.; Gandhi, Sonia; Bryant, Clare; Klenerman, David
  Acta Neuropathologica (2019), 137 (1), 103-120CODEN: ANPTAL; ISSN:0001-6322. (Springer)
  Despite the wealth of genomic and transcriptomic data in Parkinson's disease (PD), the initial mol. events are unknown. Using LD score regression anal., we show significant enrichment in PD heritability within regulatory sites for LPS-activated monocytes and that TLR4 expression is highest within human substantia nigra, the most affected brain region, suggesting a role for TLR4 inflammatory responses. We then performed extended incubation of cells with physiol. concns. of small alpha-synuclein oligomers observing the development of a TLR4-dependent sensitized inflammatory response with time, including TNF-α prodn. ROS and cell death in primary neuronal cultures were significantly reduced by TLR4 antagonists revealing that an indirect inflammatory mechanism involving cytokines produced by glial cells makes a major contribution to neuronal death. Prolonged exposure to low levels of alpha-synuclein oligomers sensitizes TLR4 responsiveness in astrocytes and microglial, explaining how they become pro-inflammatory, and may be an early causative event in PD.
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13. 13
  Li, B.; Ge, P.; Murray, K. A.; Sheth, P.; Zhang, M.; Nair, G.; Sawaya, M. R.; Shin, W. S.; Boyer, D. R.; Ye, S.; Eisenberg, D. S.; Zhou, Z. H.; Jiang, L. Cryo-EM of Full-Length α-Synuclein Reveals Fibril Polymorphs with a Common Structural Kernel. Nat. Commun. 2018, 9, 3609 DOI: 10.1038/s41467-018-05971-2
  13
  Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel
  Li Binsen; Sheth Phorum; Nair Gayatri; Shin Woo Shik; Jiang Lin; Ge Peng; Ye Shulin; Zhou Z Hong; Murray Kevin A; Zhang Meng; Sawaya Michael R; Boyer David R; Eisenberg David S; Zhou Z Hong
  Nature communications (2018), 9 (1), 3609 ISSN:.
  α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and in vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn fibrils differ in atomic structure remains elusive. Here, we present fibril polymorphs from the full-length recombinant human aSyn and their seeding capacity and cytotoxicity in vitro. By cryo-electron microscopy helical reconstruction, we determine the structures of the two predominant species, a rod and a twister, both at 3.7 ÅA resolution. Our atomic models reveal that both polymorphs share a kernel structure of a bent β-arch, but differ in their inter-protofilament interfaces. Thus, different packing of the same kernel structure gives rise to distinct fibril polymorphs. Analyses of disease-related familial mutations suggest their potential contribution to the pathogenesis of synucleinopathies by altering population distribution of the fibril polymorphs. Drug design targeting amyloid fibrils in neurodegenerative diseases should consider the formation and distribution of concurrent fibril polymorphs.
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14. 14
  Guerrero-Ferreira, R.; Taylor, N. M. I.; Mona, D.; Ringler, P.; Lauer, M. E.; Riek, R.; Britschgi, M.; Stahlberg, H. Cryo-EM Structure of Alpha-Synuclein Fibrils. eLife 2018, 7, e36402 DOI: 10.7554/eLife.36402
  14
  Cryo-EM structure of alpha-synuclein fibrils
  Guerrero-Ferreira, Ricardo; Taylor, Nicholas M. I.; Mona, Daniel; Ringler, Philippe; Lauer, Matthias E.; Riek, Roland; Britschgi, Markus; Stahlberg, Henning
  eLife (2018), 7 (), e36402/1-e36402/18CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
  Parkinson's disease is a progressive neuropathol. disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concns. in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), detd. by cryo-electron microscopy at a resoln. of 3.4 Å . Two protofilaments form a polar fibril composed of staggered b-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, contg. three of the mutation sites assocd. with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of mols. for diagnosis and treatment of synucleinopathies.
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15. 15
  Li, Y.; Zhao, C.; Luo, F.; Liu, Z.; Gui, X.; Luo, Z.; Zhang, X.; Li, D.; Liu, C.; Li, X. Amyloid Fibril Structure of α-Synuclein Determined by Cryo-Electron Microscopy. Cell Res. 2018, 28, 897– 903, DOI: 10.1038/s41422-018-0075-x
  15
  Amyloid fibril structure of α-synuclein determined by cryo-electron microscopy
  Li, Yaowang; Zhao, Chunyu; Luo, Feng; Liu, Zhenying; Gui, Xinrui; Luo, Zhipu; Zhang, Xiang; Li, Dan; Liu, Cong; Li, Xueming
  Cell Research (2018), 28 (9), 897-903CODEN: CREEB6; ISSN:1001-0602. (Nature Research)
  α-Synuclein (α-syn) amyloid fibrils are the major component of Lewy bodies, which are the pathol. hallmark of Parkinson's disease (PD) and other synucleinopathies. High-resoln. structure of α-syn fibril is important for understanding its assembly and pathol. mechanism. Here, we detd. a fibril structure of full-length α-syn (1-140) at the resoln. of 3.07 Å by cryo-electron microscopy (cryo-EM). The fibrils are cytotoxic, and transmissible to induce endogenous α-syn aggregation in primary neurons. Based on the reconstructed cryo-EM d. map, we were able to unambiguously build the fibril structure comprising residues 37-99. The α-syn amyloid fibril structure shows two protofilaments intertwining along an approx. 21 screw axis into a left-handed helix. Each protofilament features a Greek key-like topol. Remarkably, five out of the six early-onset PD familial mutations are located at the dimer interface of the fibril (H50Q, G51D, and A53T/E) or involved in the stabilization of the protofilament (E46K). Furthermore, these PD mutations lead to the formation of fibrils with polymorphic structures distinct from that of the wild-type. Our study provides mol. insight into the fibrillar assembly of α-syn at the at. level and sheds light on the mol. pathogenesis caused by familial PD mutations of α-syn.
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16. 16
  Rodriguez, J. A.; Ivanova, M. I.; Sawaya, M. R.; Cascio, D.; Reyes, F. E.; Shi, D.; Sangwan, S.; Guenther, E. L.; Johnson, L. M.; Zhang, M.; Jiang, L.; Arbing, M. A.; Nannenga, B. L.; Hattne, J.; Whitelegge, J.; Brewster, A. S.; Messerschmidt, M.; Boutet, S.; Sauter, N. K.; Gonen, T.; Eisenberg, D. S. Structure of the Toxic Core of α-Synuclein from Invisible Crystals. Nature 2015, 525, 486– 490, DOI: 10.1038/nature15368
  16
  Structure of the toxic core of α-synuclein from invisible crystals
  Rodriguez, Jose A.; Ivanova, Magdalena I.; Sawaya, Michael R.; Cascio, Duilio; Reyes, Francis E.; Shi, Dan; Sangwan, Smriti; Guenther, Elizabeth L.; Johnson, Lisa M.; Zhang, Meng; Jiang, Lin; Arbing, Mark A.; Nannenga, Brent L.; Hattne, Johan; Whitelegge, Julian; Brewster, Aaron S.; Messerschmidt, Marc; Boutet, Sebastien; Sauter, Nicholas K.; Gonen, Tamir; Eisenberg, David S.
  Nature (London, United Kingdom) (2015), 525 (7570), 486-490CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  α-Synuclein is the main component of Lewy bodies, the neuron-assocd. aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which the authors term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here, the authors describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure detn. by synchrotron x-ray diffraction, the authors used micro-electron diffraction to det. the structure at at. resoln. The 1.4-Å-resoln. structure demonstrated that this method can det. previously unknown protein structures and here yielded, to the authors' knowledge, the highest resoln. achieved by any cryo-electron microscopy method to date. The structure exhibited protofibrils built of pairs of face-to-face β-sheets. X-ray fiber diffraction patterns showed the similarity of NACore to toxic fibrils of full-length α-synuclein. The NACore structure, together with that of a 2nd segment, inspired a model for most of the ordered portion of the toxic, full-length α-synuclein fibril, presenting opportunities for the design of inhibitors of α-synuclein fibrils.
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17. 17
  Schweighauser, M.; Shi, Y.; Tarutani, A.; Kametani, F.; Murzin, A. G.; Ghetti, B.; Matsubara, T.; Tomita, T.; Ando, T.; Hasegawa, K.; Murayama, S.; Yoshida, M.; Hasegawa, M.; Scheres, S. H. W.; Goedert, M. Structures of α-Synuclein Filaments from Multiple System Atrophy. Nature 2020, 585, 464– 469, DOI: 10.1038/s41586-020-2317-6
  17
  Structures of α-synuclein filaments from multiple system atrophy
  Schweighauser, Manuel; Shi, Yang; Tarutani, Airi; Kametani, Fuyuki; Murzin, Alexey G.; Ghetti, Bernardino; Matsubara, Tomoyasu; Tomita, Taisuke; Ando, Takashi; Hasegawa, Kazuko; Murayama, Shigeo; Yoshida, Mari; Hasegawa, Masato; Scheres, Sjors H. W.; Goedert, Michel
  Nature (London, United Kingdom) (2020), 585 (7825), 464-469CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
  Synucleinopathies, which include multiple system atrophy (MSA), Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases1. Existing treatments are at best symptomatic. These diseases are characterized by the presence of, and believed to be caused by the formation of, filamentous inclusions of α-synuclein in brain cells2,3. However, the structures of α-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that α-synuclein inclusions from the brains of individuals with MSA are made of two types of filament, each of which consists of two different protofilaments. In each type of filament, non-proteinaceous mols. are present at the interface of the two protofilaments. Using two-dimensional class averaging, we show that α-synuclein filaments from the brains of individuals with MSA differ from those of individuals with DLB, which suggests that distinct conformers or strains characterize specific synucleinopathies. As is the case with tau assemblies4-9, the structures of α-synuclein filaments extd. from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain. These findings have diagnostic and potential therapeutic relevance, esp. because of the unmet clin. need to be able to image filamentous α-synuclein inclusions in the human brain.
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18. 18
  Sangwan, S.; Sahay, S.; Murray, K. A.; Morgan, S.; Guenther, E. L.; Jiang, L.; Williams, C. K.; Vinters, H. V.; Goedert, M.; Eisenberg, D. S. Inhibition of Synucleinopathic Seeding by Rationally Designed Inhibitors. eLife 2020, 9, e46775 DOI: 10.7554/eLife.46775
  18
  Inhibition of synucleinopathic seeding by rationally designed inhibitors
  Sangwan, Smriti; Sahay, Shruti; Murray, Kevin A.; Morgan, Sophie; Guenther, Elizabeth L.; Jiang, Lin; Williams, Christopher K.; Vinters, Harry V.; Goedert, Michel; Eisenberg, David S.
  eLife (2020), 9 (), e46775CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
  Seeding, in the context of amyloid disease, is the sequential transfer of pathogenic protein aggregates from cell-to-cell within affected tissues. The structure of pathogenic seeds provides the mol. basis and enables rapid conversion of sol. protein into fibrils. To date, there are no inhibitors that specifically target seeding of Parkinson's disease (PD)-assocd. asynuclein (a-syn) fibrils, in part, due to lack of information of the structural properties of pathol. seeds. Here we design small peptidic inhibitors based on the at. structure of the core of a-syn fibrils. The inhibitors prevent a-syn aggregation in vitro and in cell culture models with binding affinities of 0.5 mM to a-syn fibril seeds. The inhibitors also show efficacy in preventing seeding by human patient-derived a-syn fibrils. Our results suggest that pathogenic seeds of a-syn contain steric zippers and suggest a therapeutic approach targeted at the spread and progression that may be applicable for PD and related synucleinopathies.
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19. 19
  Priss, A.; Afitska, K.; Galkin, M.; Yushchenko, D. A.; Shvadchak, V. V. Rationally Designed Protein-Based Inhibitor of α-Synuclein Fibrillization in Cells. J. Med. Chem. 2021, 64, 6827– 6837, DOI: 10.1021/acs.jmedchem.1c00086
  19
  Rationally Designed Protein-Based Inhibitor of α-Synuclein Fibrillization in Cells
  Priss, Anastasiia; Afitska, Kseniia; Galkin, Maksym; Yushchenko, Dmytro A.; Shvadchak, Volodymyr V.
  Journal of Medicinal Chemistry (2021), 64 (10), 6827-6837CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  Misfolding of the neuronal protein α-synuclein (αSyn) into amyloid fibrils is involved in the development of Parkinson's disease (PD), and inhibition of this process is considered to be a promising therapeutic approach. In this work, we engineered protein inhibitors that bind to fibrils with higher affinity than the monomeric αSyn. They were developed based on the recent structural data of the αSyn fibrils and were shown to prevent fibril elongation upon binding to fibril ends. These inhibitors are highly selective to the misfolded αSyn, nontoxic, and active in cytosol in small concns. The best-performing inhibitor shows IC50 ~ 10 nM in a cell-based assay, which corresponds to the ~ 1:60 molar ratio to αSyn. It can suppress the formation of αSyn aggregates in cells that can be potentially used to slow down the spreading of the pathol. aggregates from cell to cell during the course of the PD.
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20. 20
  Gao, L.; Wang, W.; Wang, X.; Yang, F.; Xie, L.; Shen, J.; Brimble, M. A.; Xiao, Q.; Yao, S. Q. Fluorescent Probes for Bioimaging of Potential Biomarkers in Parkinson’s Disease. Chem. Soc. Rev. 2021, 50, 1219– 1250, DOI: 10.1039/d0cs00115e
  20
  Fluorescent probes for bioimaging of potential biomarkers in Parkinson's disease
  Gao, Liqian; Wang, Wei; Wang, Xuan; Yang, Fen; Xie, Liuxing; Shen, Jun; Brimble, Margaret A.; Xiao, Qicai; Yao, Shao Q.
  Chemical Society Reviews (2021), 50 (2), 1219-1250CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. Parkinson's disease (PD), as the second most common neurodegenerative disease, is caused by complex pathol. processes and currently remains very difficult to treat. PD brings great distress to patients and imposes a heavy economic burden on society. The no. of PD patients is growing as the aging population increases worldwide. Therefore, it is crucial to develop new tools for aiding the early diagnosis and treatment of PD. The significant pathol. features involved in PD include the abnormal accumulation of α-synuclein, metal ion dyshomeostasis, oxidative stress, mitochondrial dysfunction and neurotransmitter deficiencies. In recent years, fluorescent probes have emerged as a powerful bioimaging tool with potential to help understand the pathol. processes of PD via the detection and monitoring of pathol. features. In this review, we comprehensively summarize the design and working mechanisms of fluorescent probes along with their applications in the detection of various PD biomarkers. We also discuss the current limitations of fluorescent probes and provide perspectives on how these limitations can be overcome to develop better fluorescent probes suitable for application in clin. trials in the future. We hope that this review provides valuable information and guidance for the development of new fluorescent probes that can be used clin. in the early diagnosis of PD and contributes to the development of efficient PD drugs in the future.
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21. 21
  Ferrie, J. J.; Lengyel-Zhand, Z.; Janssen, B.; Lougee, M. G.; Giannakoulias, S.; Hsieh, C.-J.; Pagar, V. V.; Weng, C.-C.; Xu, H.; Graham, T. J. A.; Lee, V. M.-Y.; Mach, R. H.; Petersson, E. J. Identification of a Nanomolar Affinity α-Synuclein Fibril Imaging Probe by Ultra-High Throughput in Silico Screening. Chem. Sci. 2020, 11, 12746– 12754, DOI: 10.1039/d0sc02159h
  21
  Identification of a nanomolar affinity alpha-synuclein fibril imaging probe by ultra-high throughput in silico screening
  Ferrie, John J.; Lengyel-Zhand, Zsofia; Janssen, Bieneke; Lougee, Marshall G.; Giannakoulias, Sam; Hsieh, Chia-Ju; Pagar, Vinayak Vishnu; Weng, Chi-Chang; Xu, Hong; Graham, Thomas J. A.; Lee, Virginia M.-Y.; Mach, Robert H.; Petersson, E. James
  Chemical Science (2020), 11 (47), 12746-12754CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
  Small mols. that bind with high affinity and specificity to fibrils of the α-synuclein (αS) protein have the potential to serve as positron emission tomog. (PET) imaging probes to aid in the diagnosis of Parkinson's disease and related synucleinopathies. To identify such mols., we employed an ultra-high throughput in silico screening strategy using idealized pseudo-ligands termed exemplars to identify compds. for exptl. binding studies. For the top hit from this screen, we used photo-crosslinking to confirm its binding site and studied the structure-activity relationship of its analogs to develop multiple mols. with nanomolar affinity for αS fibrils and moderate specificity for α;S over Aβfibrils. Lastly, we demonstrated the potential of the lead analog as an imaging probe by measuring binding to αS-enriched homogenates from mouse brain tissue using a radiolabeled analog of the identified mols. This study demonstrates the validity of our powerful new approach to the discovery of PET probes for challenging mol. targets.
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22. 22
  Lengyel-Zhand, Z.; Ferrie, J. J.; Janssen, B.; Hsieh, C. J.; Graham, T.; Xu, K. Y.; Haney, C. M.; Lee, V. M. Y.; Trojanowski, J. Q.; Petersson, E. J.; Mach, R. H. Synthesis and Characterization of High Affinity Fluorogenic α-Synuclein Probes. Chem. Commun. 2020, 56, 3567– 3570, DOI: 10.1039/c9cc09849f
  22
  Synthesis and characterization of high affinity fluorogenic α-synuclein probes
  Lengyel-Zhand, Zsofia; Ferrie, John J.; Janssen, Bieneke; Hsieh, Chia-Ju; Graham, Thomas; Xu, Kui-ying; Haney, Conor M.; Lee, Virginia M.-Y.; Trojanowski, John Q.; Petersson, E. James; Mach, Robert H.
  Chemical Communications (Cambridge, United Kingdom) (2020), 56 (24), 3567-3570CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
  Fluorescent small mols. are powerful tools for imaging α-synuclein pathol. in vitro and in vivo. In this work, we explore benzofuranone as a potential scaffold for the design of fluorescent α-synuclein probes. These compds. have high affinity for α-synuclein, show fluorescent turn-on upon binding to fibrils, and display different binding to Lewy bodies, Lewy neurites and glial cytoplasmic inclusion pathologies in post-mortem brain tissue. These studies not only reveal the potential of benzofuranone compds. as α-synuclein specific fluorescent probes, but also have implications for the ways in which α-synucleinopathies are conformationally different and display distinct small mol. binding sites.
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23. 23
  Hsieh, C. J.; Ferrie, J. J.; Xu, K.; Lee, I.; Graham, T. J. A.; Tu, Z.; Yu, J.; Dhavale, D.; Kotzbauer, P.; Petersson, E. J.; Mach, R. H. Alpha Synuclein Fibrils Contain Multiple Binding Sites for Small Molecules. ACS Chem. Neurosci. 2018, 9, 2521– 2527, DOI: 10.1021/acschemneuro.8b00177
  23
  Alpha Synuclein Fibrils Contain Multiple Binding Sites for Small Molecules
  Hsieh, Chia-Ju; Ferrie, John J.; Xu, Kuiying; Lee, Iljung; Graham, Thomas J. A.; Tu, Zhude; Yu, Jennifer; Dhavale, Dhruva; Kotzbauer, Paul; Petersson, E. James; Mach, Robert H.
  ACS Chemical Neuroscience (2018), 9 (11), 2521-2527CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  The fibrillary aggregation of the α-synuclein (Asyn) is a hallmark of Parkinson's disease, and the identification of small mol. binding sites on fibrils is essential to the development of diagnostic imaging probes. Here, a series of mol. modeling, photoaffinity labeling, mass spectrometry,, and radioligand binding studies were conducted on Asyn fibrils. The results of these studies revealed the presence of 3 different binding sites within fibrillar Asyn capable of binding small mols. with moderate to high affinity. A knowledge of the amino acid residues in these binding sites will be important in the design of high affinity probes capable of imaging fibrillary species of Asyn.
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24. 24
  Eberling, J. L.; Dave, K. D.; Frasier, M. A. α-Synuclein Imaging: A Critical Need for Parkinson’s Disease Research. J. Parkinson’s Dis. 2013, 3, 565– 567, DOI: 10.3233/JPD-130247
  24
  α-synuclein Imaging: A Critical Need for Parkinson's Disease Research
  Eberling, Jamie L.; Dave, Kuldip D.; Frasier, Mark A.
  Journal of Parkinson's Disease (2013), 3 (4), 565-567CODEN: JPDOAP; ISSN:1877-7171. (IOS Press)
  A review. The development of an α-synuclein imaging agent could be transformative for Parkinson's disease research and drug development. The ability to image α-synuclein in the brain would enable tracking of the degree and location of pathol. over time and monitoring of therapies aimed at reducing α-synuclein levels. The Michael J. Fox Foundation has assembled a consortium of researchers to develop an α-synuclein radiotracer for use in positron emission tomog. (PET) imaging studies. While this poses a no. of challenges they should not be insurmountable and lessons learned from the development of tau radiotracers should provide valuable insights.
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25. 25
  Kulenkampff, K.; Wolf Perez, A. M.; Sormanni, P.; Habchi, J.; Vendruscolo, M. Quantifying Misfolded Protein Oligomers as Drug Targets and Biomarkers in Alzheimer and Parkinson Diseases. Nat. Rev. Chem. 2021, 5, 277– 294, DOI: 10.1038/s41570-021-00254-9
  25
  Quantifying misfolded protein oligomers as drug targets and biomarkers in Alzheimer and Parkinson diseases
  Kulenkampff, Klara; Wolf Perez, Adriana-M.; Sormanni, Pietro; Habchi, Johnny; Vendruscolo, Michele
  Nature Reviews Chemistry (2021), 5 (4), 277-294CODEN: NRCAF7; ISSN:2397-3358. (Nature Portfolio)
  A review. Protein misfolding and aggregation are characteristic of a wide range of neurodegenerative disorders, including Alzheimer and Parkinson diseases. A hallmark of these diseases is the aggregation of otherwise sol. and functional proteins into amyloid aggregates. Although for many decades such amyloid deposits have been thought to be responsible for disease progression, it is now increasingly recognized that the misfolded protein oligomers formed during aggregation are, instead, the main agents causing pathol. processes. These oligomers are transient and heterogeneous, which makes it difficult to detect and quantify them, generating confusion about their exact role in disease. The lack of suitable methods to address these challenges has hampered efforts to investigate the mol. mechanisms of oligomer toxicity and to develop oligomer-based diagnostic and therapeutic tools to combat protein misfolding diseases. In this Review, we describe methods to quantify misfolded protein oligomers, with particular emphasis on diagnostic applications as disease biomarkers and on therapeutic applications as target biomarkers. The development of these methods is ongoing, and we discuss the challenges that remain to be addressed to establish measurement tools capable of overcoming existing limitations and to meet present needs.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXosFers7s%253D&md5=d7a63b934405847347c68bd061ab34e9
26. 26
  Fayyad, M.; Salim, S.; Majbour, N.; Erskine, D.; Stoops, E.; Mollenhauer, B.; El-Agnaf, O. M. A. Parkinson’s Disease Biomarkers Based on α-Synuclein. J. Neurochem. 2019, 150, 626– 636, DOI: 10.1111/jnc.14809
  26
  Parkinson's disease biomarkers based on α-synuclein
  Fayyad, Muneera; Salim, Safa; Majbour, Nour; Erskine, Daniel; Stoops, Erik; Mollenhauer, Brit; El-Agnaf, Omar M. A.
  Journal of Neurochemistry (2019), 150 (5), 626-636CODEN: JONRA9; ISSN:0022-3042. (Wiley-Blackwell)
  A review. Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease and is estd. to affect approx. 1-4% of individuals aged over 60 years old. Although considerable efforts have been invested into developing disease-modifying therapies for Parkinson's disease, such efforts have been confounded by the difficulty in accurately diagnosing Parkinson's disease during life to enable accurate patient stratification for clin. trialling of candidate therapeutics. Therefore, the search for effective biomarkers that can be accurately evaluated during life with non-invasive means is a pressing issue in the field. Since the discovery of α-synuclein (α-syn) as a protein linked to a familial form of Parkinson's disease, later identified as the major protein component of the neuropathol. hallmark of idiopathic Parkinson's disease, considerable interest has focused on this protein and its distinct conformers. We describe here the progress that has been made in the area of Parkinson's disease biomarker discovery with a focus on α-synuclein. In particular, we highlight the novel assays that have been employed and the increasing complexity in evaluating α-synuclein with regard to the considerable diversity of conformers that exist in the biofluids and peripheral tissues under disease conditions.
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27. 27
  Brown, J. W. P.; Buell, A. K.; Michaels, T. C. T.; Meisl, G.; Carozza, J.; Flagmeier, P.; Vendruscolo, M.; Knowles, T. P. J.; Dobson, C. M.; Galvagnion, C. β-Synuclein Suppresses Both the Initiation and Amplification Steps of α-Synuclein Aggregation via Competitive Binding to Surfaces. Sci. Rep. 2016, 6, 36010 DOI: 10.1038/srep36010
  27
  β-Synuclein suppresses both the initiation and amplification steps of α-synuclein aggregation via competitive binding to surfaces
  Brown, James W. P.; Buell, Alexander K.; Michaels, Thomas C. T.; Meisl, Georg; Carozza, Jacqueline; Flagmeier, Patrick; Vendruscolo, Michele; Knowles, Tuomas P. J.; Dobson, Christopher M.; Galvagnion, Celine
  Scientific Reports (2016), 6 (), 36010CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)
  α-Synuclein is an intrinsically disordered protein that is assocd. with the pathogenesis of Parkinson's disease through the processes involved in the formation of amyloid fibrils. α and β-synuclein are homologous proteins found at comparable levels in presynaptic terminals but β-synuclein has a greatly reduced propensity to aggregate and indeed has been found to inhibit α-synuclein aggregation. In this paper, we describe how sequence differences between α- and β-synuclein affect individual microscopic processes in amyloid formation. In particular, we show that β-synuclein strongly suppresses both lipid-induced aggregation and secondary nucleation of α-synuclein by competing for binding sites at the surfaces of lipid vesicles and fibrils, resp. These results suggest that β-synuclein can act as a natural inhibitor of α-synuclein aggregation by reducing both the initiation of its self-assembly and the proliferation of its aggregates.
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28. 28
  Staats, R.; Michaels, T. C. T.; Flagmeier, P.; Chia, S.; Horne, R. I.; Habchi, J.; Linse, S.; Knowles, T. P. J.; Dobson, C. M.; Vendruscolo, M. Screening of Small Molecules Using the Inhibition of Oligomer Formation in α-Synuclein Aggregation as a Selection Parameter. Commun. Chem. 2020, 3, 191, DOI: 10.1038/s42004-020-00412-y
  28
  Screening of small molecules using the inhibition of oligomer formation in α-synuclein aggregation as a selection parameter
  Staats, Roxine; Michaels, Thomas C. T.; Flagmeier, Patrick; Chia, Sean; Horne, Robert I.; Habchi, Johnny; Linse, Sara; Knowles, Tuomas P. J.; Dobson, Christopher M.; Vendruscolo, Michele
  Communications Chemistry (2020), 3 (1), 191CODEN: CCOHCT; ISSN:2399-3669. (Nature Research)
  The aggregation of α-synuclein is a central event in Parkinsons disease and related synucleinopathies. Since pharmacol. targeting this process, however, has not yet resulted in approved disease-modifying treatments, there is an unmet need of developing novel methods of drug discovery. In this context, the use of chem. kinetics has recently enabled accurate quantifications of the microscopic steps leading to the proliferation of protein misfolded oligomers. As these species are highly neurotoxic, effective therapeutic strategies may be aimed at reducing their nos. Here, we exploit this quant. approach to develop a screening strategy that uses the reactive flux toward α-synuclein oligomers as a selection parameter. Using this approach, we evaluate the efficacy of a library of flavone derivs., identifying apigenin as a compd. that simultaneously delays and reduces the formation of α-synuclein oligomers. These results demonstrate a compd. selection strategy based on the inhibition of the formation of α-synuclein oligomers, which may be key in identifying small mols. in drug discovery pipelines for diseases assocd. with α-synuclein aggregation.
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29. 29
  Perni, M.; Flagmeier, P.; Limbocker, R.; Cascella, R.; Aprile, F. A.; Galvagnion, C.; Heller, G. T.; Meisl, G.; Chen, S. W.; Kumita, J. R.; Challa, P. K.; Kirkegaard, J. B.; Cohen, S. I. A.; Mannini, B.; Barbut, D.; Nollen, E. A. A.; Cecchi, C.; Cremades, N.; Knowles, T. P. J.; Chiti, F.; Zasloff, M.; Vendruscolo, M.; Dobson, C. M. Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine. ACS Chem. Biol. 2018, 13, 2308– 2319, DOI: 10.1021/acschembio.8b00466
  29
  Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine
  Perni, Michele; Flagmeier, Patrick; Limbocker, Ryan; Cascella, Roberta; Aprile, Francesco A.; Galvagnion, Celine; Heller, Gabriella T.; Meisl, Georg; Chen, Serene W.; Kumita, Janet R.; Challa, Pavan K.; Kirkegaard, Julius B.; Cohen, Samuel I. A.; Mannini, Benedetta; Barbut, Denise; Nollen, Ellen A. A.; Cecchi, Cristina; Cremades, Nunilo; Knowles, Tuomas P. J.; Chiti, Fabrizio; Zasloff, Michael; Vendruscolo, Michele; Dobson, Christopher M.
  ACS Chemical Biology (2018), 13 (8), 2308-2319CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
  The aggregation of α-synuclein, an intrinsically disordered protein that is highly abundant in neurons, is closely assocd. with the onset and progression of Parkinson's disease. We have shown previously that the aminosterol squalamine can inhibit the lipid induced initiation process in the aggregation of α-synuclein, and we report here that the related compd. trodusquemine is capable of inhibiting not only this process but also the fibril-dependent secondary pathways in the aggregation reaction. We further demonstrate that trodusquemine can effectively suppress the toxicity of α-synuclein oligomers in neuronal cells, and that its administration, even after the initial growth phase, leads to a dramatic redn. in the no. of α-synuclein inclusions in a Caenorhabditis elegans model of Parkinson's disease, eliminates the related muscle paralysis, and increases lifespan. On the basis of these findings, we show that trodusquemine is able to inhibit multiple events in the aggregation process of α-synuclein and hence to provide important information about the link between such events and neurodegeneration, as it is initiated and progresses. Particularly in the light of the previously reported ability of trodusquemine to cross the blood-brain barrier and to promote tissue regeneration, the present results suggest that this compd. has the potential to be an important therapeutic candidate for Parkinson's disease and related disorders.
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30. 30
  Pujols, J.; Peña-Díaz, S.; Pallarès, I.; Ventura, S. Chemical Chaperones as Novel Drugs for Parkinson’s Disease. Trends Mol. Med. 2020, 26, 408– 421, DOI: 10.1016/j.molmed.2020.01.005
  30
  Chemical Chaperones as Novel Drugs for Parkinson's Disease
  Pujols, Jordi; Pena-Diaz, Samuel; Pallares, Irantzu; Ventura, Salvador
  Trends in Molecular Medicine (2020), 26 (4), 408-421CODEN: TMMRCY; ISSN:1471-4914. (Elsevier Ltd.)
  A review. Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and the accumulation of deposits of α-synuclein (α-syn) in the brain. The pivotal role of α-syn aggregation in PD makes it an attractive target for potential disease-modifying therapies. However, the disordered nature of the protein, its multistep aggregation mechanism, and the lack of structural information on intermediate species complicate the discovery of modulators of α-syn amyloid deposition. Despite these difficulties, small mols. have been shown to block the misfolding and aggregation of α-syn, and can even disentangle mature α-syn amyloid fibrils. In this review we provide an updated overview of these leading small compds. and discuss how these chem. chaperones hold great promise to alter the course of PD progression.
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31. 31
  Gaspar, R.; Meisl, G.; Buell, A. K.; Young, L.; Kaminski, C. F.; Knowles, T. P. J.; Sparr, E.; Linse, S. Secondary Nucleation of Monomers on Fibril Surface Dominates α-Synuclein Aggregation and Provides Autocatalytic Amyloid Amplification. Q. Rev. Biophys. 2017, 50, e6 DOI: 10.1017/S0033583516000172
  31
  Secondary nucleation of monomers on fibril surface dominates α-synuclein aggregation and provides autocatalytic amyloid amplification
  Gaspar, Ricardo; Meisl, Georg; Buell, Alexander K.; Young, Laurence; Kaminski, Clemens F.; Knowles, Tuomas P. J.; Sparr, Emma; Linse, Sara
  Quarterly Reviews of Biophysics (2017), 50 (), e6/1-e6/12CODEN: QURBAW; ISSN:0033-5835. (Cambridge University Press)
  Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites contg. α-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a secondary process at mildly acidic pH, as in endosomes and other organelles. This effect manifests as a strong acceleration of the aggregation in the presence of seeds and a weak dependence of the aggregation rate on monomer concn. The mol. mechanism underlying this process could be nucleation of monomers on fibril surfaces or fibril fragmentation. Here, we aim to distinguish between these mechanisms. The nature of the secondary processes was investigated using differential sedimentation anal., trap and seed expts., quartz crystal microbalance expts. and super-resoln. microscopy. The results identify secondary nucleation of monomers on the fibril surface as the dominant secondary process leading to rapid generation of new aggregates, while no significant contribution from fragmentation was found. The newly generated oligomeric species quickly elongate to further serve as templates for secondary nucleation and this may have important implications in the spreading of PD.
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32. 32
  Michaels, T. C. T.; Lazell, H. W.; Arosio, P.; Knowles, T. P. J. Dynamics of Protein Aggregation and Oligomer Formation Governed by Secondary Nucleation. J. Chem. Phys. 2015, 143, 054901 DOI: 10.1063/1.4927655
  32
  Dynamics of protein aggregation and oligomer formation governed by secondary nucleation
  Michaels, Thomas C. T.; Lazell, Hamish W.; Arosio, Paolo; Knowles, Tuomas P. J.
  Journal of Chemical Physics (2015), 143 (5), 054901/1-054901/15CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
  The formation of aggregates in many protein systems can be significantly accelerated by secondary nucleation, a process where existing assemblies catalyze the nucleation of new species. In particular, secondary nucleation has emerged as a central process controlling the proliferation of many filamentous protein structures, including mol. species related to diseases such as sickle cell anemia and a range of neurodegenerative conditions. Increasing evidence suggests that the phys. size of protein filaments plays a key role in detg. their potential for deleterious interactions with living cells, with smaller aggregates of misfolded proteins, oligomers, being particularly toxic. It is thus crucial to progress towards an understanding of the factors that control the sizes of protein aggregates. However, the influence of secondary nucleation on the time evolution of aggregate size distributions has been challenging to quantify. This difficulty originates in large part from the fact that secondary nucleation couples the dynamics of species distant in size space. Here, we approach this problem by presenting an anal. treatment of the master equation describing the growth kinetics of linear protein structures proliferating through secondary nucleation and provide closed-form expressions for the temporal evolution of the resulting aggregate size distribution. We show how the availability of anal. solns. for the full filament distribution allows us to identify the key phys. parameters that control the sizes of growing protein filaments. Furthermore, we use these results to probe the dynamics of the populations of small oligomeric species as they are formed through secondary nucleation and discuss the implications of our work for understanding the factors that promote or curtail the prodn. of these species with a potentially high deleterious biol. activity. (c) 2015 American Institute of Physics.
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33. 33
  Chia, S.; Habchi, J.; Michaels, T. C. T.; Cohen, S. I. A.; Linse, S.; Dobson, C. M.; Knowles, T. P. J.; Vendruscolo, M. SAR by Kinetics for Drug Discovery in Protein Misfolding Diseases. Proc. Natl. Acad. Sci. U.S.A. 2018, 115, 10245– 10250, DOI: 10.1073/pnas.1807884115
  33
  SAR by kinetics for drug discovery in protein misfolding diseases
  Chia, Sean; Habchi, Johnny; Michaels, Thomas C. T.; Cohen, Samuel I. A.; Linse, Sara; Dobson, Christopher M.; Knowles, Tuomas P. J.; Vendruscolo, Michele
  Proceedings of the National Academy of Sciences of the United States of America (2018), 115 (41), 10245-10250CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compds. that inhibit the formation of protein oligomers. To achieve this goal, the authors report a structure-activity relation (SAR) approach based on chem. kinetics to est. quant. how small mols. modify the reactive flux toward oligomers. The authors use this est. to derive chem. rules in the case of the amyloid beta peptide (Aβ), which the authors then exploit to optimize starting compds. to curtail Aβ oligomer formation. The authors demonstrate this approach by converting an inactive rhodanine compd. into an effective inhibitor of Aβ oligomer formation by generating chem. derivs. in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the prodn. of protein oligomers.
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34. 34
  Le Guilloux, V.; Schmidtke, P.; Tuffery, P. Fpocket: An Open Source Platform for Ligand Pocket Detection. BMC Bioinf. 2009, 10, S6 DOI: 10.1186/1471-2105-10-168
  There is no corresponding record for this reference.
35. 35
  Buell, A. K.; Galvagnion, C.; Gaspar, R.; Sparr, E.; Vendruscolo, M.; Knowles, T. P. J.; Linse, S.; Dobson, C. M. Solution Conditions Determine the Relative Importance of Nucleation and Growth Processes in α-Synuclein Aggregation. Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 7671– 7676, DOI: 10.1073/pnas.1315346111
  35
  Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation
  Buell, Alexander K.; Galvagnion, Celine; Gaspar, Ricardo; Sparr, Emma; Vendruscolo, Michele; Knowles, Tuomas P. J.; Linse, Sara; Dobson, Christopher M.
  Proceedings of the National Academy of Sciences of the United States of America (2014), 111 (21), 7671-7676CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  The formation of amyloid fibrils by the intrinsically disordered protein α-synuclein is a hallmark of Parkinson's disease (PD). To characterize the microscopic steps in the mechanism of aggregation of this protein, the authors used in vitro aggregation assays in the presence of preformed seed fibrils to det. the mol. rate const. of fibril elongation under a range of different conditions. The authors showed that α-synuclein amyloid fibrils grew by monomer and not oligomer addn. and were subject to higher-order assembly processes that decreased their capacity to grow. The authors also found that at neutral pH under quiescent conditions homogeneous primary nucleation and secondary processes, such as fragmentation and surface-assisted nucleation, which can lead to proliferation of the total no. of aggregates, were undetectable. At pH values of <6, however, the rate of secondary nucleation increased dramatically, leading to a completely different balance between the nucleation and growth of aggregates. Thus, at mildly acidic pH values, such as those, e.g., that are present in some intracellular locations, including endosomes and lysosomes, multiplication of aggregates was much faster than at normal physiol. pH values, largely as a consequence of much more rapid secondary nucleation. These findings provide new insights into possible mechanisms of α-synuclein aggregation and aggregate spreading in the context of PD.
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36. 36
  Sterling, T.; Irwin, J. J. ZINC 15 - Ligand Discovery for Everyone. J. Chem. Inf. Model. 2015, 55, 2324– 2337, DOI: 10.1021/acs.jcim.5b00559
  36
  ZINC 15 - Ligand Discovery for Everyone
  Sterling, Teague; Irwin, John J.
  Journal of Chemical Information and Modeling (2015), 55 (11), 2324-2337CODEN: JCISD8; ISSN:1549-9596. (American Chemical Society)
  Many questions about the biol. activity and availability of small mols. remain inaccessible to investigators who could most benefit from their answers. To narrow the gap between chemoinformatics and biol., we have developed a suite of ligand annotation, purchasability, target, and biol. assocn. tools, incorporated into ZINC and meant for investigators who are not computer specialists. The new version contains over 120 million purchasable "drug-like" compds. - effectively all org. mols. that are for sale - a quarter of which are available for immediate delivery. ZINC connects purchasable compds. to high-value ones such as metabolites, drugs, natural products, and annotated compds. from the literature. Compds. may be accessed by the genes for which they are annotated as well as the major and minor target classes to which those genes belong. It offers new anal. tools that are easy for nonspecialists yet with few limitations for experts. ZINC retains its original 3D roots - all mols. are available in biol. relevant, ready-to-dock formats. ZINC is freely available at http://zinc15.docking.org.
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37. 37
  Wager, T. T.; Hou, X.; Verhoest, P. R.; Villalobos, A. Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach to Enable Alignment of Druglike Properties. ACS Chem. Neurosci. 2010, 1, 435– 449, DOI: 10.1021/cn100008c
  37
  Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties
  Wager, Travis T.; Hou, Xinjun; Verhoest, Patrick R.; Villalobos, Anabella
  ACS Chemical Neuroscience (2010), 1 (6), 435-449CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
  The interplay among commonly used physicochem. properties in drug design was examd. and utilized to create a prospective design tool focused on the alignment of key druglike attributes. Using a set of six physicochem. parameters ((a) lipophilicity, calcd. partition coeff. (ClogP); (b) calcd. distribution coeff. at pH = 7.4 (ClogD); (c) mol. wt. (MW); (d) topol. polar surface area (TPSA); (e) no. of hydrogen bond donors (HBD); (f) most basic center (pKa)), a druglikeness central nervous system multiparameter optimization (CNS MPO) algorithm was built and applied to a set of marketed CNS drugs (N = 119) and Pfizer CNS candidates (N = 108), as well as to a large diversity set of Pfizer proprietary compds. (N = 11 303). The novel CNS MPO algorithm showed that 74% of marketed CNS drugs displayed a high CNS MPO score (MPO desirability score ≥ 4, using a scale of 0-6), in comparison to 60% of the Pfizer CNS candidates. This anal. suggests that this algorithm could potentially be used to identify compds. with a higher probability of successfully testing hypotheses in the clinic. In addn., a relationship between an increasing CNS MPO score and alignment of key in vitro attributes of drug discovery (favorable permeability, P-glycoprotein (P-gp) efflux, metabolic stability, and safety) was seen in the marketed CNS drug set, the Pfizer candidate set, and the Pfizer proprietary diversity set. The CNS MPO scoring function offers advantages over hard cutoffs or utilization of single parameters to optimize structure-activity relationships (SAR) by expanding medicinal chem. design space through a holistic assessment approach. Based on six physicochem. properties commonly used by medicinal chemists, the CNS MPO function may be used prospectively at the design stage to accelerate the identification of compds. with increased probability of success.
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38. 38
  Trott, O.; Olson, A. J. AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading. J. Comput. Chem. 2009, 31, 455– 461, DOI: 10.1002/jcc.21334
  There is no corresponding record for this reference.
39. 39
  Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. J. Med. Chem. 2004, 47, 1739– 1749, DOI: 10.1021/jm0306430
  39
  Glide: A new approach for rapid, accurate docking and scoring. 1. method and assessment of docking accuracy
  Friesner, Richard A.; Banks, Jay L.; Murphy, Robert B.; Halgren, Thomas A.; Klicic, Jasna J.; Mainz, Daniel T.; Repasky, Matthew P.; Knoll, Eric H.; Shelley, Mee; Perry, Jason K.; Shaw, David E.; Francis, Perry; Shenkin, Peter S.
  Journal of Medicinal Chemistry (2004), 47 (7), 1739-1749CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
  A review. Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystd. PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 Å in nearly half of the cases and are greater than 2 Å in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.
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40. 40
  Butina, D. Unsupervised Data Base Clustering Based on Daylight’s Fingerprint and Tanimoto Similarity: A Fast and Automated Way to Cluster Small and Large Data Sets. J. Chem. Inf. Comput. Sci. 1999, 39, 747– 750, DOI: 10.1021/ci9803381
  40
  Unsupervised data base clustering based on Daylight's fingerprint and Tanimoto similarity: a fast and automated way to cluster small and large data sets
  Butina, Darko
  Journal of Chemical Information and Computer Sciences (1999), 39 (4), 747-750CODEN: JCISD8; ISSN:0095-2338. (American Chemical Society)
  Jarvis-Patrick's (J-P) algorithm is one of the most commonly used clustering algorithms within the global pharmaceutical industry. The implementation of the J-P under Daylight software, using Daylight's fingerprints and the Tanimoto similarity index, can deal with sets of 100 k mols. in a matter of a few hours. However, the J-P clustering algorithm has several assocd. problems which make it difficult to cluster large data sets in a consistent and timely manner. The clusters produced are greatly dependent on the choice of the two parameters needed to run J-P clustering, such that this method tends to produce clusters which are either very large and heterogeneous or homogeneous but too small. In any case, J-P always requires time-consuming manual tuning. An algorithm which will identify dense clusters where similarity within each cluster reflects the Tanimoto value used for the clustering and, more importantly, where the cluster centroid will be at least similar, at the given Tanimoto value, to every other mol. within the cluster in a consistent and automated manner, is presented. The similarity term used throughout the paper reflects the overall similarity between two given mols., as defined by Daylight's fingerprints and the Tanimoto similarity index.
  >> More from SciFinder ^®
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41. 41
  Flagmeier, P.; Meisl, G.; Vendruscolo, M.; Knowles, T. P. J.; Dobson, C. M.; Buell, A. K.; Galvagnion, C. Mutations Associated with Familial Parkinson’s Disease Alter the Initiation and Amplification Steps of α-Synuclein Amyloid Formation. Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 10328– 10333, DOI: 10.1073/pnas.1604645113
  41
  Mutations associated with familial Parkinson's disease alter the initiation and amplification steps of α-synuclein aggregation
  Flagmeier, Patrick; Meisl, Georg; Vendruscolo, Michele; Knowles, Tuomas P. J.; Dobson, Christopher M.; Buell, Alexander K.; Galvagnion, Celine
  Proceedings of the National Academy of Sciences of the United States of America (2016), 113 (37), 10328-10333CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Parkinson's disease is a highly debilitating neurodegenerative condition whose pathol. hallmark is the presence in nerve cells of proteinaceous deposits, known as Lewy bodies, composed primarily of amyloid fibrils of α-synuclein. Several missense mutations in the gene encoding α-synuclein have been assocd. with familial variants of Parkinson's disease and have been shown to affect the kinetics of the aggregation of the protein. Using a combination of exptl. and theor. approaches, we present a systematic in vitro study of the influence of disease-assocd. single-point mutations on the individual processes involved in α-synuclein aggregation into amyloid fibrils. We find that lipid-induced fibril prodn. and surface catalyzed fibril amplification are the processes most strongly affected by these mutations and show that familial mutations can induce dramatic changes in the crucial processes thought to be assocd. with the initiation and spreading of the aggregation of α-synuclein.
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42. 42
  Galvagnion, C.; Buell, A. K.; Meisl, G.; Michaels, T. C. T.; Vendruscolo, M.; Knowles, T. P. J.; Dobson, C. M. Lipid Vesicles Trigger α-Synuclein Aggregation by Stimulating Primary Nucleation. Nat. Chem. Biol. 2015, 11, 229– 234, DOI: 10.1038/nchembio.1750
  42
  Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation
  Galvagnion, Celine; Buell, Alexander K.; Meisl, Georg; Michaels, Thomas C. T.; Vendruscolo, Michele; Knowles, Tuomas P. J.; Dobson, Christopher M.
  Nature Chemical Biology (2015), 11 (3), 229-234CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
  α-Synuclein (α-syn) is a 140-residue intrinsically disordered protein that is involved in neuronal and synaptic vesicle plasticity, but its aggregation to form amyloid fibrils is the hallmark of Parkinson's disease (PD). The interaction between α-syn and lipid surfaces is believed to be a key feature for mediation of its normal function, but under other circumstances it is able to modulate amyloid fibril formation. Using a combination of exptl. and theor. approaches, we identify the mechanism through which facile aggregation of α-syn is induced under conditions where it binds a lipid bilayer, and we show that the rate of primary nucleation can be enhanced by three orders of magnitude or more under such conditions. These results reveal the key role that membrane interactions can have in triggering conversion of α-syn from its sol. state to the aggregated state that is assocd. with neurodegeneration and to its assocd. disease states.
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43. 43
  Michaels, T. C. T.; Cohen, S. I. A.; Vendruscolo, M.; Dobson, C. M.; Knowles, T. P. J. Hamiltonian Dynamics of Protein Filament Formation. Phys. Rev. Lett. 2016, 116, 038101, DOI: 10.1103/PhysRevLett.116.038101
  43
  Hamiltonian dynamics of protein filament formation
  Michaels, Thomas C. T.; Cohen, Samuel I. A.; Vendruscolo, Michele; Dobson, Christopher M.; Knowles, Tuomas P. J.
  Physical Review Letters (2016), 116 (3), 038101/1-038101/6CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)
  We establish the Hamiltonian structure of the rate equations describing the formation of protein filaments. We then show that this formalism provides a unified view of the behavior of a range of biol. self-assembling systems as diverse as actin. prions. and amyloidogenic polypeptides. We further demonstrate that the time-translation symmetry of the resulting Hamiltonian leads to previously unsuggested conservation laws that connect the no. and mass concns. of fibrils and allow linear growth phenomena to be equated with autocatalytic growth processes. We finally show how these results reveal simple rate laws that provide the basis for interpreting exptl. data in terms of specific mechanisms controlling the proliferation of fibrils.
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44. 44
  Palacio-Rodríguez, K.; Lans, I.; Cavasotto, C. N.; Cossio, P. Exponential Consensus Ranking Improves the Outcome in Docking and Receptor Ensemble Docking. Sci. Rep. 2019, 9, 5142 DOI: 10.1038/s41598-019-41594-3
  44
  Exponential consensus ranking improves the outcome in docking and receptor ensemble docking
  Palacio-Rodriguez Karen; Lans Isaias; Cossio Pilar; Cavasotto Claudio N; Cavasotto Claudio N; Cavasotto Claudio N; Cossio Pilar
  Scientific reports (2019), 9 (1), 5142 ISSN:.
  Consensus-scoring methods are commonly used with molecular docking in virtual screening campaigns to filter potential ligands for a protein target. Traditional consensus methods combine results from different docking programs by averaging the score or rank of each molecule obtained from individual programs. Unfortunately, these methods fail if one of the docking programs has poor performance, which is likely to occur due to training-set dependencies and scoring-function parameterization. In this work, we introduce a novel consensus method that overcomes these limitations. We combine the results from individual docking programs using a sum of exponential distributions as a function of the molecule rank for each program. We test the method over several benchmark systems using individual and ensembles of target structures from diverse protein families with challenging decoy/ligand datasets. The results demonstrate that the novel method outperforms the best traditional consensus strategies over a wide range of systems. Moreover, because the novel method is based on the rank rather than the score, it is independent of the score units, scales and offsets, which can hinder the combination of results from different structures or programs. Our method is simple and robust, providing a theoretical basis not only for molecular docking but also for any consensus strategy in general.
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45. 45
  Wilhelm, B. G.; Mandad, S.; Truckenbrodt, S.; Kröhnert, K.; Schäfer, C.; Rammner, B.; Koo, S. J.; Claßen, Ga.; Krauss, M.; Haucke, V.; Urlaub, H.; Rizzoli, S. O. Composition of Isolated Synaptic Boutons Reveals the Amounts of Vesicle Trafficking Proteins. Science 2014, 344, 1023– 1028, DOI: 10.1126/science.1252884
  45
  Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins
  Wilhelm, Benjamin G.; Mandad, Sunit; Truckenbrodt, Sven; Kroehnert, Katharina; Schaefer, Christina; Rammner, Burkhard; Koo, Seong Joo; Classen, Gala A.; Krauss, Michael; Haucke, Volker; Urlaub, Henning; Rizzoli, Silvio O.
  Science (Washington, DC, United States) (2014), 344 (6187), 1023-1028CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  Synaptic vesicle recycling has long served as a model for the general mechanisms of cellular trafficking. We used an integrative approach, combining quant. immunoblotting and mass spectrometry to det. protein nos.; electron microscopy to measure organelle nos., sizes, and positions; and super-resoln. fluorescence microscopy to localize the proteins. Using these data, we generated a three-dimensional model of an "av." synapse, displaying 300,000 proteins in at. detail. The copy nos. of proteins involved in the same step of synaptic vesicle recycling correlated closely. In contrast, copy nos. varied over more than three orders of magnitude between steps, from about 150 copies for the endosomal fusion proteins to more than 20,000 for the exocytotic ones.
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46. 46
  Yang, Y.; Shi, Y.; Schweighauser, M.; Zhang, X.; Kotecha, A.; Murzin, A. G.; Garringer, H. J.; Cullinane, P. W.; Saito, Y.; Foroud, T.; Warner, T. T.; Hasegawa, K.; Vidal, R.; Murayama, S.; Revesz, T.; Ghetti, B.; Hasegawa, M.; Lashley, T.; Scheres, S. H. W.; Goedert, M. Structures of α-synuclein filaments from human brains with Lewy pathology, Nature 2022. 610 791 795 DOI: 10.1101/2022.07.12.499706610 .
  46
  Structures of alpha synuclein filaments from human brains with Lewy pathology
  Yang, Yang; Shi, Yang; Schweighauser, Manuel; Zhang, Xianjun; Kotecha, Abhay; Murzin, Alexey G.; Garringer, Holly J.; Cullinane, Patrick W.; Saito, Yuko; Foroud, Tatiana; Warner, Thomas T.; Hasegawa, Kazuko; Vidal, Ruben; Murayama, Shigeo; Revesz, Tamas; Ghetti, Bernardino; Hasegawa, Masato; Lashley, Tammaryn; Scheres, Sjors H. W.; Goedert, Michel
  Nature (London, United Kingdom) (2022), 610 (7933), 791-795CODEN: NATUAS; ISSN:1476-4687. (Nature Portfolio)
  Parkinson disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms. Neuropathol. it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra. PD is increasingly recognized as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis. PD dementia (PDD) is clin. and neuropathol. similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, esp. oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extd. from the brains of individuals with MSA6. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct mol. conformers of assembled α-synuclein in neurodegenerative disease.
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47. 47
  Cohen, S. I. A.; Arosio, P.; Presto, J.; Kurudenkandy, F. R.; Biverstål, H.; Dolfe, L.; Dunning, C.; Yang, X.; Frohm, B.; Vendruscolo, M.; Johansson, J.; Dobson, C. M.; Fisahn, A.; Knowles, T. P. J.; Linse, S. A Molecular Chaperone Breaks the Catalytic Cycle That Generates Toxic Aβ Oligomers. Nat. Struct. Mol. Biol. 2015, 22, 207– 213, DOI: 10.1038/nsmb.2971
  47
  A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers
  Cohen, Samuel I. A.; Arosio, Paolo; Presto, Jenny; Kurudenkandy, Firoz Roshan; Biverstal, Henrik; Dolfe, Lisa; Dunning, Christopher; Yang, Xiaoting; Frohm, Birgitta; Vendruscolo, Michele; Johansson, Jan; Dobson, Christopher M.; Fisahn, Andre; Knowles, Tuomas P. J.; Linse, Sara
  Nature Structural & Molecular Biology (2015), 22 (3), 207-213CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
  Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been assocd. with aggregation of the amyloid-β peptide (Aβ42). Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a mol. chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiol. expts. These results reveal that mol. chaperones can help maintain protein homeostasis by selectively suppressing crit. microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.
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48. 48
  Perni, M.; Galvagnion, C.; Maltsev, A.; Meisl, G.; Müller, M. B. D.; Challa, P. K.; Kirkegaard, J. B.; Cohen, S. I. A.; Cascella, R.; Chen, S. W.; Limboker, R.; Sormanni, P.; Heller, G. T.; Francesco, A.; Cremades, N.; Cecchi, C.; Chiti, F.; Ellen, A. A.; Knowles, T. P. J.; Vendruscolo, M.; Bax, A.; Zasloff, M.; Dobson, C. M.; Perni, M.; Galvagnion, C.; Maltsev, A.; Meisl, G.; Müller, M. B. D.; Challa, P. K.; Julius, B.; Flagmeier, P.; Cohen, S. I. A.; Chen, S. W.; Limbocker, R.; Sormanni, P.; Heller, G. T.; Aprile, F. A.; Cremades, N.; Cecchi, C.; Chiti, F.; Nollen, E. A. A.; Tuomas, P. J.; Vendruscolo, M.; Bax, A.; Dobson, C. M.; Perni, M.; Galvagnion, C.; Maltsev, A.; Meisl, G.; Müller, M. B. D.; Challa, P. K. A Natural Product Inhibits the Initiation of α-Synuclein Aggregation and Suppresses Its Toxicity. Proc. Natl. Acad. Sci. U.S.A. 2017, 114, E1009– E1017, DOI: 10.1073/pnas.1610586114
  48
  A natural product inhibits the initiation of α-synuclein aggregation and suppresses its toxicity
  Perni, Michele; Galvagnion, Celine; Maltsev, Alexander; Meisl, Georg; Muller, Martin B. D.; Challa, Pavan K.; Kirkegaard, Julius B.; Flagmeier, Patrick; Cohen, Samuel I. A.; Cascella, Roberta; Chen, Serene W.; Limboker, Ryan; Sormanni, Pietro; Heller, Gabriella T.; Aprile, Francesco A.; Cremades, Nunilo; Cecchi, Cristina; Chiti, Fabrizio; Nollen, Ellen A. A.; Knowles, Tuomas P. J.; Vendruscolo, Michele; Bax, Adriaan; Zasloff, Michael; Dobson, Christopher M.
  Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (6), E1009-E1017CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  The self-assembly of α-synuclein is closely assocd. with Parkinson's disease and related syndromes. The authors show that squalamine, a natural product with known anticancer and antiviral activity, dramatically affects α-synuclein aggregation in vitro and in vivo. The authors elucidate the mechanism of action of squalamine by investigating its interaction with lipid vesicles, which are known to stimulate nucleation, and find that this compd. displaces α-synuclein from the surfaces of such vesicles, thereby blocking the first steps in its aggregation process. The authors also show that squalamine almost completely suppresses the toxicity of α-synuclein oligomers in human neuroblastoma cells by inhibiting their interactions with lipid membranes. The authors further examine the effects of squalamine in a Caenorhabditis elegans strain overexpressing α-synuclein, observing a dramatic redn. of α-synuclein aggregation and an almost complete elimination of muscle paralysis. These findings suggest that squalamine could be a means of therapeutic intervention in Parkinson's disease and related conditions.
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49. 49
  Agerschou, E. D.; Flagmeier, P.; Saridaki, T.; Galvagnion, C.; Komnig, D.; Heid, L.; Prasad, V.; Shaykhalishahi, H.; Willbold, D.; Dobson, C. M.; Voigt, A.; Falkenburger, B.; Hoyer, W.; Buell, A. K. An Engineered Monomer Binding-Protein for α-Synuclein Efficiently Inhibits the Proliferation of Amyloid Fibrils. eLife 2019, 8, e46112 DOI: 10.7554/eLife.46112
  49
  An engineered monomer binding-protein for α-synuclein efficiently inhibits the proliferation of amyloid fibrils
  Agerschou, Emil Dandanell; Flagmeier, Patrick; Saridaki, Theodora; Galvagnion, Celine; Komnig, Daniel; Heid, Laetitia; Prasad, Vibha; Shaykhalishahi, Hamed; Willbold, Dieter; Dobson, Christopher M.; Voigt, Aaron; Falkenburger, Bjoern; Hoyer, Wolfgang; Buell, Alexander K.
  eLife (2019), 8 (), e46112/1-e46112/31CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)
  Removing or preventing the formation of α-synuclein aggregates is a plausible strategy against Parkinson's disease. To this end, we have engineered the β-wrapin AS69 to bind monomeric α-synuclein with high affinity. In cultured cells, AS69 reduced the self-interaction of α-synuclein and formation of visible α-synuclein aggregates. In flies, AS69 reduced α-synuclein aggregates and the locomotor deficit resulting from α-synuclein expression in neuronal cells. In biophys. expts. in vitro, AS69 highly sub-stoichiometrically inhibited both primary and autocatalytic secondary nucleation processes, even in the presence of a large excess of monomer. We present evidence that the AS69-α-synuclein complex, rather than the free AS69, is the inhibitory species responsible for sub-stoichiometric inhibition of secondary nucleation. These results represent a new paradigm that high affinity monomer binders can lead to strongly substoichiometric inhibition of nucleation processes.
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50. 50
  Linse, S.; Scheidt, T.; Bernfur, K.; Vendruscolo, M.; Dobson, C. M.; Cohen, S. I. A.; Sileikis, E.; Lundqvist, M.; Qian, F.; O’Malley, T.; Bussiere, T.; Weinreb, P. H.; Xu, C. K.; Meisl, G.; Devenish, S. R. A.; Knowles, T. P. J.; Hansson, O. Kinetic Fingerprints Differentiate the Mechanisms of Action of Anti-Aβ Antibodies. Nat. Struct. Mol. Biol. 2020, 27, 1125– 1133, DOI: 10.1038/s41594-020-0505-6
  50
  Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies
  Linse, Sara; Scheidt, Tom; Bernfur, Katja; Vendruscolo, Michele; Dobson, Christopher M.; Cohen, Samuel I. A.; Sileikis, Eimantas; Lundqvist, Martin; Qian, Fang; O'Malley, Tiernan; Bussiere, Thierry; Weinreb, Paul H.; Xu, Catherine K.; Meisl, Georg; Devenish, Sean R. A.; Knowles, Tuomas P. J.; Hansson, Oskar
  Nature Structural & Molecular Biology (2020), 27 (12), 1125-1133CODEN: NSMBCU; ISSN:1545-9993. (Nature Research)
  The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer's disease, has driven many therapeutic efforts for the past 20 years. Failures of clin. trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irresp. of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quant. binding measurements to address the mechanism of action of four clin. stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the prodn. of oligomeric aggregates and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ. Our results reveal that, uniquely among these four antibodies, aducanumab dramatically reduces the flux of Aβ oligomers.
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- PDB: 6cu7
Supporting Information
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.2c00548.
- Predicted binding affinity of compounds via computational docking; TEM images of α-synuclein fibrils formed in the presence of molecules; kinetic profiles of α-synuclein aggregation in the presence of molecules; time dependence of reactive flux toward α-synuclein oligomers in the presence of molecules; fluorescence emission spectra of molecule C; colocalization of molecules with α-synuclein fibrils in the presence of neuroblastoma cells; list of all molecules from docking studies experimentally validated; and supplementary methods, supplementary figures, and supplementary table (PDF)
- mp2c00548_si_001.pdf (1.58 MB)
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Structure-Based Discovery of Small-Molecule Inhibitors of the Autocatalytic Proliferation of α-Synuclein AggregatesClick to copy article linkArticle link copied!

Molecular Pharmaceutics

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Abstract

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Introduction

Materials and Methods

Computational Docking

Preparation of Compounds and Chemicals

Preparation of α-Synuclein

Preparation of α-Synuclein Fibril Seeds

Kinetic Assays

Transmission Electron Microscopy (TEM)

Determination of the Elongation Rate Constant

Determination of the Fibril Amplification Rate Constant

Determination of the Oligomer Flux

Fluorescence Polarization

Mass Spectrometry

Cell Cultures

Colocalization Assay

Results

Framework to Identify Compounds That Bind α-Synuclein Fibrils

Figure 1

In Silico Docking of Compounds Predicted to Bind α-Synuclein Fibrils

Identification of Compounds That Inhibit α-Synuclein Secondary Nucleation

Figure 2

Figure 3

Kinetic Analysis of α-Synuclein Aggregation in the Presence of the Inhibitors

Figure 4

Compound C Inhibits α-Synuclein Oligomer Formation

Figure 5

Compound C Binds α-Synuclein Fibrils

Discussion

Supporting Information

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References

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Molecular Pharmaceutics

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Abstract

Figure 1

Figure 2

Figure 3

Figure 4

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References

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Structure-Based Discovery of Small-Molecule Inhibitors of the Autocatalytic Proliferation of α-Synuclein Aggregates
Click to copy article linkArticle link copied!