Unraveling the Structure and Dynamics of Ac-PHF6-NH₂ Tau Segment Oligomers

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This article references 60 other publications.

1. 1

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   The amyloid state and its association with protein misfolding diseases

   Knowles, Tuomas P. J.; Vendruscolo, Michele; Dobson, Christopher M.

   Nature Reviews Molecular Cell Biology (2014), 15 (6), 384-396CODEN: NRMCBP; ISSN:1471-0072. (Nature Publishing Group)

   A review. The phenomenon of protein aggregation and amyloid formation has become the subject of rapidly increasing research activities across a wide range of scientific disciplines. Such activities have been stimulated by the assocn. of amyloid deposition with a range of debilitating medical disorders, from Alzheimer's disease to type II diabetes, many of which are major threats to human health and welfare in the modern world. It has become clear, however, that the ability to form the amyloid state is more general than previously imagined, and that its study can provide unique insights into the nature of the functional forms of peptides and proteins, as well as understanding the means by which protein homeostasis can be maintained and protein metastasis avoided.

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   Role of tau protein in both physiological and pathological conditions

   Avila, Jesus; Lucas, Jose J.; Perez, Mar; Hernandez, Felix

   Physiological Reviews (2004), 84 (2), 361-384CODEN: PHREA7; ISSN:0031-9333. (American Physiological Society)

   A review. The morphol. of a neuron is detd. by its cytoskeletal scaffolding. Thus proteins that assoc. with the principal cytoskeletal components such as the microtubules have a strong influence on both the morphol. and physiol. of neurons. Tau is a microtubule-assocd. protein that stabilizes neuronal microtubules under normal physiol. conditions. However, in certain pathol. situations, tau protein may undergo modifications, mainly through phosphorylation, that can result in the generation of aberrant aggregates that are toxic to neurons. This process occurs in a no. of neurol. disorders collectively known as tauopathies, the most commonly recognized of which is Alzheimer's disease. The purpose of this review is to define the role of tau protein under normal physiol. conditions and to highlight the role of the protein in different tauopathies.

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   Rankin, C. A.; Sun, Q.; Gamblin, T. C. Tau Phosphorylation by GSK-3β Promotes Tangle-like Filament Morphology. Mol. Neurodegener. 2007, 2 (1), 12  DOI: 10.1186/1750-1326-2-12

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   Nizynski, B.; Dzwolak, W.; Nieznanski, K. Amyloidogenesis of Tau Protein. Protein Sci. 2017, 26 (11), 2126– 2150,  DOI: 10.1002/pro.3275

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   Amyloidogenesis of Tau protein

   Nizynski, Bartosz; Dzwolak, Wojciech; Nieznanski, Krzysztof

   Protein Science (2017), 26 (11), 2126-2150CODEN: PRCIEI; ISSN:1469-896X. (Wiley-Blackwell)

   The role of microtubule-assocd. protein Tau in neurodegeneration has been extensively investigated since the discovery of Tau amyloid aggregates in the brains of patients with Alzheimer's disease (AD). The process of formation of amyloid fibrils is known as amyloidogenesis and attracts much attention as a potential target in the prevention and treatment of neurodegenerative conditions linked to protein aggregation. Cerebral deposition of amyloid aggregates of Tau is obsd. not only in AD but also in numerous other tauopathies and prion diseases. Amyloidogenesis of intrinsically unstructured monomers of Tau can be triggered by mutations in the Tau gene, post-translational modifications, or interactions with polyanionic mols. and aggregation-prone proteins/peptides. The self-assembly of amyloid fibrils of Tau shares a no. of characteristic features with amyloidogenesis of other proteins involved in neurodegenerative diseases. For example, in vitro expts. have demonstrated that the nucleation phase, which is the rate-limiting stage of Tau amyloidogenesis, is shortened in the presence of fragmented preformed Tau fibrils acting as aggregation templates ("seeds"). Accordingly, Tau aggregates released by tauopathy-affected neurons can spread the neurodegenerative process in the brain through a prion-like mechanism, originally described for the pathogenic form of prion protein. Moreover, Tau has been shown to form amyloid strains-structurally diverse self-propagating aggregates of potentially various pathol. effects, resembling in this respect prion strains. Here, we review the current literature on Tau aggregation and discuss mechanisms of propagation of Tau amyloid in the light of the prion-like paradigm.

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   Iqbal, K.; del C Alonso, A.; Chen, S.; Chohan, M. O.; El-Akkad, E.; Gong, C.-X.; Khatoon, S.; Li, B.; Liu, F.; Rahman, A.; Tanimukai, H.; Grundke-Iqbal, I. Tau Pathology in Alzheimer Disease and Other Tauopathies. Biochim. Biophys. Acta, Mol. Basis Dis. 2005, 1739 (2), 198– 210,  DOI: 10.1016/j.bbadis.2004.09.008

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   Tau pathology in Alzheimer disease and other tauopathies

   Iqbal, Khalid; Del C. Alonso, Alejandra; Chen, She; Chohan, M. Omar; El-Akkad, Ezzat; Gong, Cheng-Xin; Khatoon, Sabiha; Li, Bin; Liu, Fei; Rahman, Abdur; Tanimukai, Hitoshi; Grundke-Iqbal, Inge

   Biochimica et Biophysica Acta, Molecular Basis of Disease (2005), 1739 (2-3), 198-210CODEN: BBADEX; ISSN:0925-4439. (Elsevier B.V.)

   A review. Just as neuronal activity is essential to normal brain function, microtubule-assocd. protein tau appears to be crit. to normal neuronal activity in the mammalian brain, esp. in the evolutionarily most advanced species, the Homo sapiens. While the loss of functional tau can be compensated by the other two neuronal microtubule-assocd. proteins, MAP1A/MAP1B and MAP2, it is the dysfunctional, i.e., the toxic tau, which forces an affected neuron in a long and losing battle resulting in a slow but progressive retrograde neurodegeneration. It is this pathol. which is characteristic of Alzheimer disease (AD) and other tauopathies. To date, the most established and the most compelling cause of dysfunctional tau in AD and other tauopathies is the abnormal hyperphosphorylation of tau. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but also in a gain of a toxic function whereby the pathol. tau sequesters normal tau, MAP1A/MAP1B and MAP2, and causes inhibition and disruption of microtubules. This toxic gain of function of the pathol. tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation converts it functionally into a normal-like state. The affected neurons battle the toxic tau both by continually synthesizing new normal tau as well as by packaging the abnormally hyperphosphorylated tau into inert polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. Slowly but progressively, the affected neurons undergo a retrograde degeneration. The hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases and tau phosphatases and as well as changes in tau's conformation which affect its interaction with these enzymes. A decrease in the activity of protein phosphatase-2A (PP-2A) in AD brain and certain missense mutations seen in frontotemporal dementia promotes the abnormal hyperphosphorylation of tau. Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.

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   Lasagna-Reeves, C. A.; Castillo-Carranza, D. L.; Guerrero-Muñoz, M. J.; Jackson, G. R.; Kayed, R. Preparation and Characterization of Neurotoxic Tau Oligomers. Biochemistry 2010, 49 (47), 10039– 10041,  DOI: 10.1021/bi1016233

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   Preparation and Characterization of Neurotoxic Tau Oligomers

   Lasagna-Reeves, Cristian A.; Castillo-Carranza, Diana L.; Guerrero-Munoz, Marcos J.; Jackson, George R.; Kayed, Rakez

   Biochemistry (2010), 49 (47), 10039-10041CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

   Tau aggregation is a pathol. hallmark of Alzheimer's disease, Parkinson's disease, and many other neurodegenerative disorders known as tauopathies. Tau aggregates take on many forms, and their formation is a multistage process with intermediate stages. Recently, tau oligomers have emerged as the pathogenic species in tauopathies and a possible mediator of amyloid-β toxicity in Alzheimer's disease. Here, we use a novel, physiol. relevant method (oligomer cross-seeding) to prep. homogeneous populations of tau oligomers and characterize these oligomers in vitro. We show that both Aβ and α-synuclein oligomers induce tau aggregation and the formation of β-sheet-rich neurotoxic tau oligomers.

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   Castillo-Carranza, D. L.; Gerson, J. E.; Sengupta, U.; Guerrero-Muñoz, M. J.; Lasagna-Reeves, C. A.; Kayed, R. Specific Targeting of Tau Oligomers in Htau Mice Prevents Cognitive Impairment and Tau Toxicity Following Injection with Brain-Derived Tau Oligomeric Seeds. J. Alzheimer’s Dis. 2014, 40 (s1), S97– S111,  DOI: 10.3233/JAD-132477

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   Specific Targeting of Tau Oligomers in Htau Mice Prevents Cognitive Impairment and Tau Toxicity Following Injection with Brain-Derived Tau Oligomeric Seeds

   Medina, Miguel; Avila, Jesus; Castillo-Carranza, Diana L.; Gerson, Julia E.; Sengupta, Urmi; Guerrero-Munoz, Marcos J.; Lasagna-Reeves, Cristian A.; Kayed, Rakez

   Journal of Alzheimer's Disease (2014), 40 (Suppl. 1), S97-S111CODEN: JADIF9; ISSN:1387-2877. (IOS Press)

   Neurodegenerative disease is one of the greatest health crises in the world and as life expectancy rises, the no. of people affected will continue to increase. The most common neurodegenerative disease, Alzheimer's disease, is a tauopathy, characterized by the presence of aggregated tau, namely in the form of neurofibrillary tangles. Historically, neurofibrillary tangles have been considered the main tau species of interest in Alzheimer's disease; however, we and others have shown that tau oligomers may be the most toxic form and the species responsible for the spread of pathol. We developed a novel anti-tau oligomer-specific mouse monoclonal antibody (TOMA) and investigated the potential of anti-tau oligomer passive immunization in preventing the toxicity of tau pathol. in Htau mice. We injected pure brain-derived tau oligomers intracerebrally in 3-mo-old wild-type and Htau mice and investigated the protective effects of a single 60 μg TOMA injection when compared to the same dose of non-specific IgG and found that TOMA conferred protection against the accumulation of tau oligomers and cognitive deficits for up to 1 mo after treatment. Addnl., we injected pure brain-derived tau oligomers intracerebrally in 3-mo-old wild-type and Htau mice and treated animals with biweekly injections of 60 μg TOMA or non-specific IgG. We found that long-term administration of TOMA was effective as a preventative therapy, inhibiting oligomeric tau and preserving memory function. These results support the crit. role of oligomeric tau in disease progression and validate tau oligomers as a potential drug target.

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   Ward, S. M.; Himmelstein, D. S.; Lancia, J. K.; Binder, L. I. Tau Oligomers and Tau Toxicity in Neurodegenerative Disease. Biochem. Soc. Trans. 2012, 40 (4), 667– 671,  DOI: 10.1042/BST20120134

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   Tau oligomers and tau toxicity in neurodegenerative disease

   Ward, Sarah M.; Himmelstein, Diana S.; Lancia, Jody K.; Binder, Lester I.

   Biochemical Society Transactions (2012), 40 (4), 667-671CODEN: BCSTB5; ISSN:0300-5127. (Portland Press Ltd.)

   A review. AD (Alzheimer's disease) is a progressive neurodegenerative disorder characterized by the extracellular accumulation of amyloid β-peptide and the intracellular accumulation of tau. Although there is much evidence linking tau to neurodegeneration, the precise mechanism of tau-mediated neurotoxicity remains elusive. The presence of tau-pos. pre-tangle neurons lacking neurofibrillary tangles has been reported in AD brain tissue. In order to study this non-fibrillar tau, we generated a novel monoclonal antibody, named TOC1 (tau oligomeric complex 1), which selectively labels tau dimers and oligomers, but does not label filaments. Time-course anal. and antibody labeling indicates that oligomers appear as an early event in AD pathogenesis. Using a squid axoplasm assay, we have demonstrated that aggregated tau inhibits anterograde FAT (fast axonal transport), whereas monomeric tau has no effect. This inhibition requires a small stretch of N-terminal amino acids termed the PAD (phosphatase-activation domain). Using a PAD-specific antibody, TNT1 (tau N-terminal 1), we demonstrate that PAD exposure is increased in diseased neurons and this leads to an increase in FAT inhibition. Antibody co-labeling with the early-AD marker AT8 indicates that, similar to TOC1, TNT1 expression represents an early event in AD pathogenesis. Finally, the effects of the mol. chaperone Hsp70 (heat-shock protein 70) were also investigated within the squid axoplasm assay. We illustrate that Hsp70 preferentially binds to tau oligomers over filaments and prevents anterograde FAT inhibition obsd. with a mixt. of both forms of aggregated tau. Together, these findings support the hypothesis that tau oligomers are the toxic form of tau in neurodegenerative disease.

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   Pérez, M.; Valpuesta, J. M.; Medina, M.; Montejo de Garcini, E.; Avila, J. Polymerization of τ into Filaments in the Presence of Heparin: The Minimal Sequence Required for τ - τ Interaction. J. Neurochem. 1996, 67 (3), 1183– 1190,  DOI: 10.1046/j.1471-4159.1996.67031183.x

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    Kampers, T.; Friedhoff, P.; Biernat, J.; Mandelkow, E.-M.; Mandelkow, E. RNA Stimulates Aggregation of Microtubule-Associated Protein Tau into Alzheimer-like Paired Helical Filaments. FEBS Lett. 1996, 399 (3), 344– 349,  DOI: 10.1016/S0014-5793(96)01386-5

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    RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments

    Kampers, T.; Friedhoff, P.; Biernat, J.; Mandelkow, E.-M.; Mandelkow, E.

    FEBS Letters (1996), 399 (3), 344-349CODEN: FEBLAL; ISSN:0014-5793. (Elsevier)

    The microtubule-assocd. protein tau is the main component of the paired helical filaments (PHFs) of Alzheimer's disease, the most common senile dementia. To understand the origin of tau's abnormal assembly the authors have studied the influence of other cytosolic components. Here the authors report that PHF assembly is strongly enhanced by RNA. The RNA-induced assembly of PHFs is dependent on the formation of intermol. disulfide bridges involving Cys322 in the third repeat of tau, and it includes the dimerization of tau as an early intermediate. Three-repeat constructs polymerize most efficiently, two repeat constructs are the min. no. required for assembly, and even all six full-length isoforms of tau can be induced to form PHFs by RNA.

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11. 11

    Pretti, E.; Shell, M. S. Mapping the Configurational Landscape and Aggregation Phase Behavior of the Tau Protein Fragment PHF6. Proc. Natl. Acad. Sci. U.S.A. 2023, 120 (48), e2309995120  DOI: 10.1073/pnas.2309995120

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    Arosio, P.; Knowles, T. P. J.; Linse, S. On the Lag Phase in Amyloid Fibril Formation. Phys. Chem. Chem. Phys. 2015, 17 (12), 7606– 7618,  DOI: 10.1039/C4CP05563B

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    On the lag phase in amyloid fibril formation

    Arosio, Paolo; Knowles, Tuomas P. J.; Linse, Sara

    Physical Chemistry Chemical Physics (2015), 17 (12), 7606-7618CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)

    A review. The formation of nanoscale amyloid fibrils from normally sol. peptides and proteins is a common form of self-assembly phenomenon that has fundamental connections with biol. functions and human diseases. The kinetics of this process has been widely studied and exhibits on a macroscopic level three characteristic stages: (1) a lag phase; (2) a growth phase; and (3) a final plateau regime. The question of which mol. events take place during each one of these phases has been a central element in the quest for a mechanism of amyloid formation. Here, the authors discuss the nature and mol. origin of the lag-phase in amyloid formation by making use of tools and concepts from phys. chem., in particular from chem. reaction kinetics. The authors discuss how, in macroscopic samples, it has become apparent that the lag-phase is not a waiting time for nuclei to form. Rather, multiple parallel processes exist and typically millions of primary nuclei form during the lag phase from monomers in soln. Thus, the lag-time represents a time that is required for the nuclei that are formed early on in the reaction to grow and proliferate in order to reach an aggregate concn. that is readily detected in bulk assays. In many cases, this proliferation takes place through secondary nucleation, where fibrils may present a catalytic surface for the formation of new aggregates. Fibrils may also break (fragmentation) and thereby provide new ends for elongation. Thus, at least 2 (primary nucleation and elongation) and in many systems at least 4 (primary nucleation, elongation, secondary nucleation, and fragmentation) microscopic processes occur during the lag phase. Moreover, these same processes occur during all 3 phases of the macroscopic aggregation process, albeit at different rates as governed by rate consts. and by the concn. of reacting species at each point in time.

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13. 13

    Cohen, S. I. A.; Vendruscolo, M.; Dobson, C. M.; Knowles, T. P. J. From Macroscopic Measurements to Microscopic Mechanisms of Protein Aggregation. J. Mol. Biol. 2012, 421 (2–3), 160– 171,  DOI: 10.1016/j.jmb.2012.02.031

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    From Macroscopic Measurements to Microscopic Mechanisms of Protein Aggregation

    Cohen, Samuel I. A.; Vendruscolo, Michele; Dobson, Christopher M.; Knowles, Tuomas P. J.

    Journal of Molecular Biology (2012), 421 (2-3), 160-171CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)

    A review. The ability to relate bulk exptl. measurements of amyloid formation to the microscopic assembly processes that underlie protein aggregation is crit. to achieve a quant. understanding of this complex phenomenon. In this review, the authors focus on the insights from classical and modern theories of linear growth phenomena and discuss how theory allows the roles of growth and nucleation processes to be defined through the anal. of exptl. in vitro time courses of amyloid formation. Moreover, the authors discuss the specific signatures in the time course of the reactions that correspond to the actions of primary and secondary nucleation processes and outline strategies for identifying and characterizing the nature of the dominant process responsible in each case for the generation of new aggregates. The authors highlight the power of a global anal. of exptl. time courses acquired under different conditions, and discuss how such an anal. allows a rigorous connection to be established between the macroscopic measurements and the rates of the individual microscopic processes that underlie the phenomenon of amyloid formation.

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14. 14

    Rodriguez Camargo, D. C.; Sileikis, E.; Chia, S.; Axell, E.; Bernfur, K.; Cataldi, R. L.; Cohen, S. I. A.; Meisl, G.; Habchi, J.; Knowles, T. P. J.; Vendruscolo, M.; Linse, S. Proliferation of Tau 304–380 Fragment Aggregates through Autocatalytic Secondary Nucleation. ACS Chem. Neurosci. 2021, 12 (23), 4406– 4415,  DOI: 10.1021/acschemneuro.1c00454

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    14

    Proliferation of Tau 304-380 Fragment Aggregates through Autocatalytic Secondary Nucleation

    Rodriguez Camargo, Diana C.; Sileikis, Eimantas; Chia, Sean; Axell, Emil; Bernfur, Katja; Cataldi, Rodrigo L.; Cohen, Samuel I. A.; Meisl, Georg; Habchi, Johnny; Knowles, Tuomas P. J.; Vendruscolo, Michele; Linse, Sara

    ACS Chemical Neuroscience (2021), 12 (23), 4406-4415CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)

    The self-assembly of the protein tau into neurofibrillary tangles is one of the hallmarks of Alzheimer's disease and related tauopathies. Still, the mol. mechanism of tau aggregation is largely unknown. This problem may be addressed by systematically obtaining reproducible in vitro kinetic measurements under quiescent conditions in the absence of triggering substances. Here, the authors implement this strategy by developing protocols for obtaining an ultrapure tau fragment (residues 304-380 of tau441) and for performing spontaneous aggregation assays with reproducible kinetics under quiescent conditions. The authors are thus able to identify the mechanism of fibril formation of the tau 304-380 fragment at physiol. pH using fluorescence spectroscopy and mass spectrometry. Primary nucleation is slow, and secondary processes dominate the aggregation process once the initial aggregates are formed. Moreover, the authors' results further show that secondary nucleation of monomers on fibril surfaces dominate over fragmentation of fibrils. Using sep. isotopes in monomers and fibrils, through mass spectroscopy measurements, the authors verify the isotope compn. of the intermediate oligomeric species, which reveals that these small aggregates were generated from monomer through secondary nucleation. The authors' results provide a framework for understanding the processes leading to tau aggregation in disease, and for selecting possible tau forms as targets in the development of therapeutic interventions in Alzheimer's disease.

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15. 15

    Lövestam, S.; Li, D.; Wagstaff, J. L.; Kotecha, A.; Kimanius, D.; McLaughlin, S. H.; Murzin, A. G.; Freund, S. M. V.; Goedert, M.; Scheres, S. H. W. Disease-Specific Tau Filaments Assemble via Polymorphic Intermediates. Nature 2024, 625 (7993), 119– 125,  DOI: 10.1038/s41586-023-06788-w

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    Abdul Vahid, A.; Oliyantakath Hassan, M. S.; Sahayaraj, A. E.; Babu, A. T.; Kizhakkeduth, S. T.; Vijayan, V. Modulation of Primary and Secondary Processes in Tau Fibril Formation by Salt-Induced Dynamics. ACS Chem. Neurosci. 2024, 15 (6), 1242– 1253,  DOI: 10.1021/acschemneuro.3c00852

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17. 17

    Younan, N. D.; Viles, J. H. A Comparison of Three Fluorophores for the Detection of Amyloid Fibers and Prefibrillar Oligomeric Assemblies. ThT (Thioflavin T); ANS (1-Anilinonaphthalene-8-Sulfonic Acid); and bisANS (4,4’-Dianilino-1,1’-Binaphthyl-5,5′-Disulfonic Acid). Biochemistry 2015, 54 (28), 4297– 4306,  DOI: 10.1021/acs.biochem.5b00309

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    A Comparison of Three Fluorophores for the Detection of Amyloid Fibers and Prefibrillar Oligomeric Assemblies. ThT (Thioflavin T); ANS (1-Anilinonaphthalene-8-sulfonic Acid); and bisANS (4,4'-Dianilino-1,1'-binaphthyl-5,5'-disulfonic Acid)

    Younan, Nadine D.; Viles, John H.

    Biochemistry (2015), 54 (28), 4297-4306CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)

    Amyloid fiber formation is a key event in many misfolding disorders. The ability to monitor the kinetics of fiber formation and other prefibrillar assemblies is therefore crucial for understanding these diseases. Here the authors compare three fluorescent probes for their ability to monitor fiber formation, ANS (1-anilinonaphthalene-8-sulfonic acid) and bis-ANS (4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid) along with the more widely used thioflavin T (ThT). For this, the authors used two highly amyloidogenic peptides: amyloid-β (Aβ) from Alzheimer's disease and assocd. with type II diabetes. Using a well-plate reader, the authors show all three fluorophores can report the kinetics of fiber formation. Indeed, bis-ANS is markedly more sensitive to fiber detection than ThT and has a submicromolar affinity for Aβ fibers. Furthermore, fluorescence detection is very sensitive to the presence of excess fluorophore. In particular, beyond a 1:1 stoichiometry these probes demonstrate marked fluorescence quenching, for both Aβ and IAPP. Indeed, the fiber-assocd. fluorescence signal is almost completely quenched in the presence of excess ThT. There is also intense interest in the detection of prefibrillar amyloid assemblies, as oligomers and protofibrils are believed to be highly cytotoxic. The authors generate stable, fiber-free, prefibrillar assemblies of Aβ and survey their fluorescence with ANS and bis-ANS. Fluorescence from ANS has often been used as a marker for oligomers; however, the authors show ANS can fluoresce more strongly in the presence of fibers and should therefore be used as a probe for oligomers with caution.

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    Meisl, G.; Kirkegaard, J. B.; Arosio, P.; Michaels, T. C. T.; Vendruscolo, M.; Dobson, C. M.; Linse, S.; Knowles, T. P. J. Molecular Mechanisms of Protein Aggregation from Global Fitting of Kinetic Models. Nat. Protoc. 2016, 11 (2), 252– 272,  DOI: 10.1038/nprot.2016.010

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    18

    Molecular mechanisms of protein aggregation from global fitting of kinetic models

    Meisl, Georg; Kirkegaard, Julius B.; Arosio, Paolo; Michaels, Thomas C. T.; Vendruscolo, Michele; Dobson, Christopher M.; Linse, Sara; Knowles, Tuomas P. J.

    Nature Protocols (2016), 11 (2), 252-272CODEN: NPARDW; ISSN:1750-2799. (Nature Publishing Group)

    The elucidation of the mol. mechanisms by which sol. proteins convert into their amyloid forms is a fundamental prerequisite for understanding and controlling disorders that are linked to protein aggregation, such as Alzheimer's and Parkinson's diseases. However, because of the complexity assocd. with aggregation reaction networks, the anal. of kinetic data of protein aggregation to obtain the underlying mechanisms represents a complex task. Here we describe a framework, using quant. kinetic assays and global fitting, to det. and to verify a mol. mechanism for aggregation reactions that is compatible with exptl. kinetic data. We implement this approach in a web-based software, AmyloFit. Our procedure starts from the results of kinetic expts. that measure the concn. of aggregate mass as a function of time. We illustrate the approach with results from the aggregation of the β-amyloid (Aβ) peptides measured using thioflavin T, but the method is suitable for data from any similar kinetic expt. measuring the accumulation of aggregate mass as a function of time; the input data are in the form of a tab-sepd. text file. We also outline general exptl. strategies and practical considerations for obtaining kinetic data of sufficient quality to draw detailed mechanistic conclusions, and the procedure starts with instructions for extensive data quality control. For the core part of the anal., we provide an online platform (http://www.amylofit.ch.cam.ac.uk) that enables robust global anal. of kinetic data without the need for extensive programming or detailed math. knowledge. The software automates repetitive tasks and guides users through the key steps of kinetic anal.: detn. of constraints to be placed on the aggregation mechanism based on the concn. dependence of the aggregation reaction, choosing from several fundamental models describing assembly into linear aggregates and fitting the chosen models using an advanced minimization algorithm to yield the reaction orders and rate consts. Finally, we outline how to use this approach to investigate which targets potential inhibitors of amyloid formation bind to and where in the reaction mechanism they act. The protocol, from processing data to detg. mechanisms, can be completed in <1 d.

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19. 19

    Cohen, S. I. A.; Linse, S.; Luheshi, L. M.; Hellstrand, E.; White, D. A.; Rajah, L.; Otzen, D. E.; Vendruscolo, M.; Dobson, C. M.; Knowles, T. P. J. Proliferation of Amyloid-B42 Aggregates Occurs through a Secondary Nucleation Mechanism. Proc. Natl. Acad. Sci. U.S.A. 2013, 110 (24), 9758– 9763,  DOI: 10.1073/pnas.1218402110

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    19

    Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism

    Cohen, Samuel I. A.; Linse, Sara; Luheshi, Leila M.; Hellstrand, Erik; White, Duncan A.; Rajah, Luke; Otzen, Daniel E.; Vendruscolo, Michele; Dobson, Christopher M.; Knowles, Tuomas P. J.

    Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (24), 9758-9763, S9758/1-S9758/11CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    The generation of toxic oligomers during the aggregation of the amyloid-β (Aβ) peptide Aβ42 into amyloid fibrils and plaques has emerged as a central feature of the onset and progression of Alzheimer's disease, but the mol. pathways that control pathol. aggregation have proved challenging to identify. Here, the authors used a combination of kinetic studies, selective radiolabeling expts., and cell viability assays to detect directly the rates of formation of both fibrils and oligomers and the resulting cytotoxic effects. The results showed that once a small but crit. concn. of amyloid fibrils had accumulated, the toxic oligomeric species were predominantly formed from monomeric peptide mols. through a fibril-catalyzed secondary nucleation reaction, rather than through a classical mechanism of homogeneous primary nucleation. This catalytic mechanism coupled together the growth of insol. amyloid fibrils and the generation of diffusible oligomeric aggregates that are implicated as neurotoxic agents in Alzheimer's disease. These results revealed that the aggregation of Aβ42 is promoted by a pos. feedback loop that originates from the interactions between the monomeric and fibrillar forms of this peptide. These findings bring together the main mol. species implicated in the Aβ aggregation cascade and suggest that perturbation of the secondary nucleation pathway identified in this study could be an effective strategy to control the proliferation of neurotoxic Aβ42 oligomers.

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20. 20

    Hovanová, V.; Hovan, A.; Žoldák, G.; Sedlák, E.; Humenik, M. Global Analysis of Kinetics Reveals the Role of Secondary Nucleation in Recombinant Spider Silk Self-Assembly. Protein Sci. 2023, 32 (8), e4722  DOI: 10.1002/pro.4722

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    There is no corresponding record for this reference.
21. 21

    Xu, Y.; Maya-Martinez, R.; Guthertz, N.; Heath, G. R.; Manfield, I. W.; Breeze, A. L.; Sobott, F.; Foster, R.; Radford, S. E. Tuning the Rate of Aggregation of hIAPP into Amyloid Using Small-Molecule Modulators of Assembly. Nat. Commun. 2022, 13 (1), 1040  DOI: 10.1038/s41467-022-28660-7

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    There is no corresponding record for this reference.
22. 22

    Dear, A. J.; Michaels, T. C. T.; Meisl, G.; Klenerman, D.; Wu, S.; Perrett, S.; Linse, S.; Dobson, C. M.; Knowles, T. P. J. Kinetic Diversity of Amyloid Oligomers. Proc. Natl. Acad. Sci. U.S.A. 2020, 117 (22), 12087– 12094,  DOI: 10.1073/pnas.1922267117

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    22

    Kinetic diversity of amyloid oligomers

    Dear, Alexander J.; Michaels, Thomas C. T.; Meisl, Georg; Klenerman, David; Wu, Si; Perrett, Sarah; Linse, Sara; Dobson, Christopher M.; Knowles, Tuomas P. J.

    Proceedings of the National Academy of Sciences of the United States of America (2020), 117 (22), 12087-12094CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)

    The spontaneous assembly of proteins into amyloid fibrils is a phenomenon central to many increasingly common and currently incurable human disorders, including Alzheimer's and Parkinson's diseases. Oligomeric species form transiently during this process and not only act as essential intermediates in the assembly of new filaments but also represent major pathogenic agents in these diseases. While amyloid fibrils possess a common, defining set of physicochem. features, oligomers, by contrast, appear much more diverse, and their commonalities and differences have hitherto remained largely unexplored. Here, we use the framework of chem. kinetics to investigate their dynamical properties. By fitting exptl. data for several unrelated amyloidogenic systems to newly derived mechanistic models, we find that oligomers present with a remarkably wide range of kinetic and thermodn. stabilities but that they possess two properties that are generic: they are overwhelmingly nonfibrillar, and they predominantly dissoc. back to monomers rather than maturing into fibrillar species. These discoveries change our understanding of the relationship between amyloid oligomers and amyloid fibrils and have important implications for the nature of their cellular toxicity.

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23. 23

    Shammas, S. L.; Garcia, G. A.; Kumar, S.; Kjaergaard, M.; Horrocks, M. H.; Shivji, N.; Mandelkow, E.; Knowles, T. P. J.; Mandelkow, E.; Klenerman, D. A Mechanistic Model of Tau Amyloid Aggregation Based on Direct Observation of Oligomers. Nat. Commun. 2015, 6 (1), 7025  DOI: 10.1038/ncomms8025

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    23

    A mechanistic model of tau amyloid aggregation based on direct observation of oligomers

    Shammas, Sarah L.; Garcia, Gonzalo A.; Kumar, Satish; Kjaergaard, Magnus; Horrocks, Mathew H.; Shivji, Nadia; Mandelkow, Eva; Knowles, Tuomas P. J.; Mandelkow, Eckhard; Klenerman, David

    Nature Communications (2015), 6 (), 7025CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

    Protein aggregation plays a key role in neurodegenerative disease, giving rise to small oligomers that may become cytotoxic to cells. The fundamental microscopic reactions taking place during aggregation, and their rate consts., have been difficult to det. due to lack of suitable methods to identify and follow the low concn. of oligomers over time. Here we use single-mol. fluorescence to study the aggregation of the repeat domain of tau (K18), and two mutant forms linked with familial frontotemporal dementia, the deletion mutant ΔK280 and the point mutant P301L. Our kinetic anal. reveals that aggregation proceeds via monomeric assembly into small oligomers, and a subsequent slow structural conversion step before fibril formation. Using this approach, we have been able to quant. det. how these mutations alter the aggregation energy landscape.

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24. 24

    Kjaergaard, M.; Dear, A. J.; Kundel, F.; Qamar, S.; Meisl, G.; Knowles, T. P. J.; Klenerman, D. Oligomer Diversity during the Aggregation of the Repeat Region of Tau. ACS Chem. Neurosci. 2018, 9 (12), 3060– 3071,  DOI: 10.1021/acschemneuro.8b00250

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    24

    Oligomer Diversity during the Aggregation of the Repeat Region of Tau

    Kjaergaard, Magnus; Dear, Alexander J.; Kundel, Franziska; Qamar, Seema; Meisl, Georg; Knowles, Tuomas P. J.; Klenerman, David

    ACS Chemical Neuroscience (2018), 9 (12), 3060-3071CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)

    The mol. mechanism of protein aggregation is of both fundamental and clin. importance as amyloid aggregates are linked to a no. of neurodegenerative disorders. Such protein aggregates include macroscopic insol. fibrils as well as small sol. oligomeric species. Time-dependent resoln. of these species is prerequisite for a detailed quant. understanding of protein aggregation; this remains challenging due to the lack of methods for detecting and characterizing transient and heterogeneous protein oligomers. Here, we used single-mol. fluorescence techniques combined with mechanistic modeling to study the heparin-induced aggregation of the repeat region of tau protein, which forms the core region of neurofibrillary tangles found in Alzheimer's disease. We distinguished several sub-populations of oligomers with different stability and followed their evolution during aggregation reactions as a function of temp. and concn. The employment of techniques from chem. kinetics revealed that the 2 largest populations were structurally distinct from fibrils; and were both kinetically and thermodynamically unstable. The 1st population was in rapid exchange with monomers and held together by electrostatic interactions; the 2nd was kinetically more stable, dominated at later times, and was probably off-pathway to fibril formation. These more stable oligomers may contribute to other oligomer-induced effects in the cellular environment; e.g., by overloading protein quality control systems. We also showed that the shortest growing filaments remained suspended in aq. buffer and thus comprised a 3rd, smaller population of transient oligomers with cross-β structure. Overall, our data showed that a diverse population of oligomers of different structures and half-lives are formed during the aggregation reaction with the great majority of oligomers formed not going on to form fibrils.

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25. 25

    Cawood, E. E.; Karamanos, T. K.; Wilson, A. J.; Radford, S. E. Visualizing and Trapping Transient Oligomers in Amyloid Assembly Pathways. Biophys. Chem. 2021, 268, 106505  DOI: 10.1016/j.bpc.2020.106505

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    25

    Visualizing and trapping transient oligomers in amyloid assembly pathways

    Cawood, Emma E.; Karamanos, Theodoros K.; Wilson, Andrew J.; Radford, Sheena E.

    Biophysical Chemistry (2021), 268 (), 106505CODEN: BICIAZ; ISSN:0301-4622. (Elsevier B.V.)

    Oligomers which form during amyloid fibril assembly are considered to be key contributors towards amyloid disease. However, understanding how such intermediates form, their structure, and mechanisms of toxicity presents significant challenges due to their transient and heterogeneous nature. Here, we discuss two different strategies for addressing these challenges: use of (1) methods capable of detecting lowly-populated species within complex mixts., such as NMR, single particle methods (including fluorescence and force spectroscopy), and mass spectrometry; and (2) chem. and biol. tools to bias the amyloid energy landscape towards specific oligomeric states. While the former methods are well suited to following the kinetics of amyloid assembly and obtaining low-resoln. structural information, the latter are capable of producing oligomer samples for high-resoln. structural studies and inferring structure-toxicity relationships. Together, these different approaches should enable a clearer picture to be gained of the nature and role of oligomeric intermediates in amyloid formation and disease.

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26. 26

    Kováč, A.; Majerová, P.; Nytka, M.; Cechová, M. Z.; Bednář, P.; Hájek, R.; Cooper-Shepherd, D. A.; Muck, A.; Lemr, K. Separation of Isomeric Tau Phosphopeptides from Alzheimer’s Disease Brain by Cyclic Ion Mobility Mass Spectrometry. J. Am. Soc. Mass Spectrom. 2023, 34 (3), 394– 400,  DOI: 10.1021/jasms.2c00289

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    26

    Separation of Isomeric Tau Phosphopeptides from Alzheimer's Disease Brain by Cyclic Ion Mobility Mass Spectrometry

    Kovac, Andrej; Majerova, Petra; Nytka, Marianna; Cechova, Monika Zajacova; Bednar, Petr; Hajek, Roman; Cooper-Shepherd, Dale A.; Muck, Alexander; Lemr, Karel

    Journal of the American Society for Mass Spectrometry (2023), 34 (3), 394-400CODEN: JAMSEF; ISSN:1879-1123. (American Chemical Society)

    Alzheimer's disease (AD) is a neurodegenerative disorder of increasing concern. It belongs to diseases termed tauopathies which are characterized by inclusions of abnormally hyperphosphorylated and truncated forms of the protein tau. Studies of tauopathies often focus on detection and characterization of these aberrant tau proteoforms, in particular the phosphorylation sites, which represent a significant anal. challenge for example when several phosphosites can be present on the same peptide. Such isomers can even be difficult to fully sep. chromatog. Since recently introduced cyclic ion mobility-mass spectrometry can offer different selectivity, we have investigated the closely positioned phosphorylation sites S214, T212, and T217 of a tryptic peptide from proline rich region of tau-TPSLPTPPTREPK. The conformational heterogeneity of the isomeric peptides in the gas phase hindered their sepn. due to their overlapping arrival time distributions. Increasing the resoln. of the anal. alone is insufficient to distinguish the peptides in a mixt. typical of patient samples. We therefore developed a method based on a combination of collision-induced dissocn., isomeric product ions (m/z 677) mobility sepn. and post-mobility dissocn. to aid in analyzing the isomeric phosphopeptides of tau in diseased brain ext. For all three isomers (T212, S214, and T217), the ion mobility signal of the ion at m/z 677 was still observable at the concn. of 0.1 nmol/L. This work not only offers insights into the phosphorylation of tau protein in AD but also provides an anal. workflow for the characterization of challenging pathol. protein modifications in neurodegenerative diseases.

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27. 27

    Nshanian, M.; Lantz, C.; Wongkongkathep, P.; Schrader, T.; Klärner, F.-G.; Blümke, A.; Despres, C.; Ehrmann, M.; Smet-Nocca, C.; Bitan, G.; Loo, J. A. Native Top-Down Mass Spectrometry and Ion Mobility Spectrometry of the Interaction of Tau Protein with a Molecular Tweezer Assembly Modulator. J. Am. Soc. Mass Spectrom. 2019, 30 (1), 16– 23,  DOI: 10.1007/s13361-018-2027-6

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    27

    Native Top-Down Mass Spectrometry and Ion Mobility Spectrometry of the Interaction of Tau Protein with a Molecular Tweezer Assembly Modulator

    Nshanian, Michael; Lantz, Carter; Wongkongkathep, Piriya; Schrader, Thomas; Klarner, Frank-Gerrit; Blumke, Anika; Despres, Clement; Ehrmann, Michael; Smet-Nocca, Caroline; Bitan, Gal; Loo, Joseph A.

    Journal of the American Society for Mass Spectrometry (2019), 30 (1), 16-23CODEN: JAMSEF; ISSN:1044-0305. (Springer)

    Native top-down mass spectrometry (MS) and ion mobility spectrometry (IMS) were applied to characterize the interaction of a mol. tweezer assembly modulator, CLR01, with tau, a protein believed to be involved in a no. of neurodegenerative disorders, including Alzheimer's disease. The tweezer CLR01 has been shown to inhibit aggregation of amyloidogenic polypeptides without toxic side effects. ESI-MS spectra for different forms of tau protein (full-length, fragments, phosphorylated, etc.) in the presence of CLR01 indicate a primary binding stoichiometry of 1:1. The relatively high charging of the protein measured from nondenaturing solns. is typical of intrinsically disordered proteins, such as tau. Top-down mass spectrometry using electron capture dissocn. (ECD) is a tool used to det. not only the sites of posttranslational modifications but also the binding site(s) of noncovalent interacting ligands to biomols. The intact protein and the protein-modulator complex were subjected to ECD-MS to obtain sequence information, map phosphorylation sites, and pinpoint the sites of inhibitor binding. The ESI-MS study of intact tau proteins indicates that top-down MS is amenable to the study of various tau isoforms and their posttranslational modifications (PTMs). The ECD-MS data point to a CLR01 binding site in the microtubule-binding region of tau, spanning residues K294-K331, which includes a six-residue nucleating segment PHF6 (VQIVYK) implicated in aggregation. Furthermore, ion mobility expts. on the tau fragment in the presence of CLR01 and phosphorylated tau reveal a shift towards a more compact structure. The mass spectrometry study suggests a picture for the mol. mechanism of the modulation of protein-protein interactions in tau by CLR01.

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28. 28

    Larini, L.; Gessel, M. M.; Lapointe, N. E.; Do, T. D.; Bowers, M. T.; Feinstein, S. C.; Shea, J. E. Initiation of Assembly of Tau(273–284) and Its ΔK280 Mutant: An Experimental and Computational Study. Phys. Chem. Chem. Phys. 2013, 15 (23), 8916– 8928,  DOI: 10.1039/c3cp00063j

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    There is no corresponding record for this reference.
29. 29

    Ganguly, P.; Do, T. D.; Larini, L.; Lapointe, N. E.; Sercel, A. J.; Shade, M. F.; Feinstein, S. C.; Bowers, M. T.; Shea, J.-E. Tau Assembly: The Dominant Role of PHF6 (VQIVYK) in Microtubule Binding Region Repeat R3. J. Phys. Chem. B 2015, 119 (3), 4582– 4593,  DOI: 10.1021/acs.jpcb.5b00175

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    There is no corresponding record for this reference.
30. 30

    Huang, R. Y.-C.; Iacob, R. E.; Sankaranarayanan, S.; Yang, L.; Ahlijanian, M.; Tao, L.; Tymiak, A. A.; Chen, G. Probing Conformational Dynamics of Tau Protein by Hydrogen/Deuterium Exchange Mass Spectrometry. J. Am. Soc. Mass Spectrom. 2018, 29 (1), 174– 182,  DOI: 10.1007/s13361-017-1815-8

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    30

    Probing Conformational Dynamics of Tau Protein by Hydrogen/Deuterium Exchange Mass Spectrometry

    Huang, Richard Y.-C.; Iacob, Roxana E.; Sankaranarayanan, Sethu; Yang, Ling; Ahlijanian, Michael; Tao, Li; Tymiak, Adrienne A.; Chen, Guodong

    Journal of the American Society for Mass Spectrometry (2018), 29 (1), 174-182CODEN: JAMSEF; ISSN:1044-0305. (Springer)

    Fibrillization of the microtubule-assocd. protein tau has been recognized as one of the signature pathologies of the nervous system in Alzheimer's disease, progressive supranuclear palsy, and other tauopathies. The conformational transition of tau in the fibrillization process, tau monomer to sol. aggregates to fibrils in particular, remains unclear. Here we report on the use of hydrogen/deuterium exchange mass spectrometry (HDX-MS) in combination with other biochem. approaches, including Thioflavin S fluorescence measurements, ELISA, and Western blotting to understand the heparin-induced tau's fibrillization. HDX-MS studies including anti-tau antibody epitope mapping expts. provided mol. level details of the full-length tau's conformational dynamics and its regional solvent accessibility upon sol. aggregates formation. The results demonstrate that R3 region in the full-length tau's microtubule binding repeat region (MTBR) is stabilized in the aggregation process, leaving both N and C terminal regions to be solvent exposed in the sol. aggregates and fibrils. The findings also illustrate the practical utility of orthogonal anal. methodologies for the characterization of protein higher order structure. [Figure not available: see fulltext.].

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31. 31

    Chen, D.; Drombosky, K. W.; Hou, Z.; Sari, L.; Kashmer, O. M.; Ryder, B. D.; Perez, V. A.; Woodard, D. R.; Lin, M. M.; Diamond, M. I.; Joachimiak, L. A. Tau Local Structure Shields an Amyloid-Forming Motif and Controls Aggregation Propensity. Nat. Commun. 2019, 10 (1), 2493  DOI: 10.1038/s41467-019-10355-1

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    31

    Tau local structure shields an amyloid-forming motif and controls aggregation propensity

    Chen Dailu; Drombosky Kenneth W; Hou Zhiqiang; Kashmer Omar M; Ryder Bryan D; Perez Valerie A; Woodard DaNae R; Diamond Marc I; Joachimiak Lukasz A; Chen Dailu; Ryder Bryan D; Perez Valerie A; Sari Levent; Lin Milo M; Sari Levent; Lin Milo M; Joachimiak Lukasz A

    Nature communications (2019), 10 (1), 2493 ISSN:.

    Tauopathies are neurodegenerative diseases characterized by intracellular amyloid deposits of tau protein. Missense mutations in the tau gene (MAPT) correlate with aggregation propensity and cause dominantly inherited tauopathies, but their biophysical mechanism driving amyloid formation is poorly understood. Many disease-associated mutations localize within tau's repeat domain at inter-repeat interfaces proximal to amyloidogenic sequences, such as (306)VQIVYK(311). We use cross-linking mass spectrometry, recombinant protein and synthetic peptide systems, in silico modeling, and cell models to conclude that the aggregation-prone (306)VQIVYK(311) motif forms metastable compact structures with its upstream sequence that modulates aggregation propensity. We report that disease-associated mutations, isomerization of a critical proline, or alternative splicing are all sufficient to destabilize this local structure and trigger spontaneous aggregation. These findings provide a biophysical framework to explain the basis of early conformational changes that may underlie genetic and sporadic tau pathogenesis.

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32. 32

    Vaden, T. D.; Gowers, S. A. N.; Snoek, L. C. Observation of β-Sheet Aggregation in a Gas-Phase Tau-Peptide Dimer. J. Am. Chem. Soc. 2009, 131 (7), 2472– 2474,  DOI: 10.1021/ja807760d

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    32

    Observation of β-Sheet Aggregation in a Gas-Phase Tau-Peptide Dimer

    Vaden, Timothy D.; Gowers, Sally A. N.; Snoek, Lavina C.

    Journal of the American Chemical Society (2009), 131 (7), 2472-2474CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    In Alzheimer's disease, the tau protein forms intracellular amyloid fibrils in which the 306VQIVYK311 sequence adopts parallel β-sheets, enabling fibril formation via cross-β "steric zippers". We investigated aggregation of the protected segment (Ac-VQIVYK-NHMe) using IR/UV hole-burning spectroscopy in the NH stretch region in a cold mol. beam combined with DFT calcns. in order to characterize its structure and identify the noncovalent interactions generally responsible for aggregation and stabilization in amyloid peptides. The computed and exptl. IR spectra suggest that the tau-protein fragments form extended β-strands that are combined in a β-sheet through characteristic backbone hydrogen bonds, indicating that this secondary structure is energetically most attractive and readily forms in the gas phase, without any "guiding" interactions from a solvent or protein environment.

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33. 33

    Seo, J.; Hoffmann, W.; Warnke, S.; Huang, X.; Gewinner, S.; Schöllkopf, W.; Bowers, M. T.; Von Helden, G.; Pagel, K. An Infrared Spectroscopy Approach to Follow β-Sheet Formation in Peptide Amyloid Assemblies. Nat. Chem. 2017, 9 (1), 39– 44,  DOI: 10.1038/nchem.2615

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    33

    An infrared spectroscopy approach to follow β-sheet formation in peptide amyloid assemblies

    Seo, Jongcheol; Hoffmann, Waldemar; Warnke, Stephan; Huang, Xing; Gewinner, Sandy; Schoellkopf, Wieland; Bowers, Michael T.; von Helden, Gert; Pagel, Kevin

    Nature Chemistry (2017), 9 (1), 39-44CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)

    Amyloidogenic peptides and proteins play a crucial role in a variety of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. These proteins undergo a spontaneous transition from a sol., often partially folded form, into insol. amyloid fibrils that are rich in β-sheets. Increasing evidence suggests that highly dynamic, polydisperse folding intermediates, which occur during fibril formation, are the toxic species in the amyloid-related diseases. Traditional condensed-phase methods are of limited use for characterizing these states because they typically only provide ensemble avs. rather than information about individual oligomers. Here we report the first direct secondary-structure anal. of individual amyloid intermediates using a combination of ion mobility spectrometry-mass spectrometry (IMS-MS) and gas-phase IR spectroscopy. Our data reveal that oligomers of the fibril-forming peptide segments VEALYL and YVEALL, which consist of 4-9 peptide strands, can contain a significant amt. of β-sheet. In addn., our data show that the more-extended variants of each oligomer generally exhibit increased β-sheet content.

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34. 34

    Von Bergen, M.; Friedhoff, P.; Biernat, J.; Heberle, J.; Mandelkow, E.-M.; Mandelkow, E. Assembly of τ Protein into Alzheimer Paired Helical Filaments Depends on a Local Sequence Motif (³⁰⁶ VQIVYK ³¹¹) Forming β Structure. Proc. Natl. Acad. Sci. U.S.A. 2000, 97 (10), 5129– 5134,  DOI: 10.1073/pnas.97.10.5129

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    There is no corresponding record for this reference.
35. 35

    Lövestam, S.; Koh, F. A.; van Knippenberg, B.; Kotecha, A.; Murzin, A. G.; Goedert, M.; Scheres, S. H. Assembly of Recombinant Tau into Filaments Identical to Those of Alzheimer’s Disease and Chronic Traumatic Encephalopathy. eLife 2022, 11, e76494  DOI: 10.7554/eLife.76494

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    35

    Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy

    Lovestam, Sofia; Koh, Fujiet Adrian; Van Knippenberg, Bart; Kotecha, Abhay; Murzin, Alexey G.; Goedert, Michel; Scheres, Sjors H. W.

    eLife (2022), 11 (), e76494CODEN: ELIFA8; ISSN:2050-084X. (eLife Sciences Publications Ltd.)

    Abundant filamentous inclusions of tau are characteristic of more than 20 neurodegenerative diseases that are collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of tau amyloid filaments from human brain revealed that distinct tau folds characterize many different diseases. A lack of lab.-based model systems to generate these structures has hampered efforts to uncover the mol. mechanisms that underlie tauopathies. Here, we report in vitro assembly conditions with recombinant tau that replicate the structures of filaments from both Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE), as detd. by cryo-EM. Our results suggest that post-translational modifications of tau modulate filament assembly, and that previously obsd. addnl. densities in AD and CTE filaments may arise from the presence of inorg. salts, like phosphates and sodium chloride. In vitro assembly of tau into disease-relevant filaments will facilitate studies to det. their roles in different diseases, as well as the development of compds. that specifically bind to these structures or prevent their formation.

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36. 36

    Stroganova, I.; Willenberg, H.; Tente, T.; Depraz Depland, A.; Bakels, S.; Rijs, A. M. Exploring the Aggregation Propensity of PHF6 Peptide Segments of the Tau Protein Using Ion Mobility Mass Spectrometry Techniques. Anal. Chem. 2024, 96 (13), 5115– 5124,  DOI: 10.1021/acs.analchem.3c04974

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37. 37

    KrishnaKumar, V. G.; Paul, A.; Gazit, E.; Segal, D. Mechanistic Insights into Remodeled Tau-Derived PHF6 Peptide Fibrils by Naphthoquinone-Tryptophan Hybrids. Sci. Rep. 2018, 8 (1), 71  DOI: 10.1038/s41598-017-18443-2

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    37

    Mechanistic insights into remodeled Tau-derived PHF6 peptide fibrils by Naphthoquinone-Tryptophan hybrids

    KrishnaKumar V Guru; Paul Ashim; Gazit Ehud; Segal Daniel; KrishnaKumar V Guru; Gazit Ehud; Segal Daniel

    Scientific reports (2018), 8 (1), 71 ISSN:.

    Intra-cellular tau protein tangles and extra-cellular β-amyloid plaques are hallmarks of Alzheimer's disease (AD), characterized by the conversion of natively unfolded monomeric protein/peptide into misfolded β-sheet rich aggregates. Therefore, inhibiting the aggregation cascade or disassembling the pre-formed aggregates becomes a pivotal event in disease treatment. In the present study, we show that Naphthoquinone-Tryptophan hybrids, i.e., NQTrp and Cl-NQTrp significantly disrupted the pre-formed fibrillar aggregates of Tau-derived PHF6 (VQIVYK) peptide and full-length tau protein in vitro, in a dose-dependent manner as evident from ThS assay, CD spectroscopy, and TEM. Molecular dynamics simulation of PHF6 oligomers and fibrils with the Naphthoquinone-Tryptophan hybrids provides a possible structure-function based mechanism-of-action, highlighting the role of hydrophobic interaction and hydrogen bond formation during fibril disassembly. These findings signify the effectiveness of NQTrp and Cl-NQTrp in disassembling fibrillar aggregates and may help in designing novel hybrid molecules for AD treatment.

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38. 38

    Goux, W. J.; Kopplin, L.; Nguyen, A. D.; Leak, K.; Rutkofsky, M.; Shanmuganandam, V. D.; Sharma, D.; Inouye, H.; Kirschner, D. A. The Formation of Straight and Twisted Filaments from Short Tau Peptides *. J. Biol. Chem. 2004, 279 (26), 26868– 26875,  DOI: 10.1074/jbc.M402379200

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39. 39

    Arya, S.; Ganguly, P.; Arsiccio, A.; Claud, S. L.; Trapp, B.; Schonfeld, G. E.; Liu, X.; Cantrell, K. L.; Shea, J.-E.; Bowers, M. T. Terminal Capping of an Amyloidogenic Tau Fragment Modulates Its Fibrillation Propensity. J. Phys. Chem. B 2020, 124 (40), 8772– 8783,  DOI: 10.1021/acs.jpcb.0c05768

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    39

    Terminal Capping of an Amyloidogenic Tau Fragment Modulates Its Fibrillation Propensity

    Arya, Shruti; Ganguly, Pritam; Arsiccio, Andrea; Claud, Sarah L.; Trapp, Benjamin; Schonfeld, Grace E.; Liu, Xikun; Lazar Cantrell, Kristi; Shea, Joan-Emma; Bowers, Michael T.

    Journal of Physical Chemistry B (2020), 124 (40), 8772-8783CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    Aberrant protein folding giving characteristic cross-β-sheet-rich amyloid structures is known for its assocn. with a variety of debilitating human diseases. Often, depending upon amino acid compn., only a small segment of a large protein participates in amyloid formation and is in fact capable of self-assembling into amyloid, independent of the rest of the protein. Therefore, such peptide fragments serve as useful model systems for understanding the process of amyloid formation. An important factor that has often been overlooked while using peptides to mimic full-length protein is the charge on the termini of these peptides. Here, the authors show the influence of terminal charges on the aggregation of an amyloidogenic peptide from microtubule-assocd. protein Tau, implicated in Alzheimer's disease and tauopathies. Modification of terminal charges by capping the peptide at one or both of the termini drastically modulates the fibrillation of the hexapeptide sequence paired helical filament 6 (PHF6) from repeat 3 of Tau, both with and without heparin. Without heparin, the PHF6 peptide capped at both termini and PHF6 capped only at the N-terminus self-assembled to form amyloid fibrils. With heparin, all capping variants of PHF6, except for PHF6 with both termini free, formed typical amyloid fibrils. However, the rate and extent of aggregation both with and without heparin as well as the morphol. of aggregates are highly dependent on the terminal charges. The authors' mol. dynamics simulations on PHF6 capping variants corroborated the authors' expts. and provided crit. insights into the mechanism of PHF6 self-assembly. Overall, the authors' results emphasize the importance of terminal modifications in fibrillation of small peptide fragments and provide significant insights into the aggregation of a small Tau fragment, which is considered essential for Tau filament assembly.

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40. 40

    Siemion, I. Z.; Cebrat, M.; Jankowski, A.; Lisowski, M.; Pfdyczak, A.; Wyslsouch, A. Does the Edge-to-face Interaction between Aromatic Rings Occur in Cyclolinopeptide A Analogues?. Int. J. Pept. Protein Res. 1994, 44 (1), 61– 69,  DOI: 10.1111/j.1399-3011.1994.tb00405.x

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    Hirata, A.; Sugimoto, K.; Konno, T.; Morii, T. Amyloid-Forming Propensity of the Hydrophobic Non-Natural Amino Acid on the Fibril-Forming Core Peptide of Human Tau. Bioorg. Med. Chem. Lett. 2007, 17 (11), 2971– 2974,  DOI: 10.1016/j.bmcl.2007.03.071

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    Dodds, J. N.; Baker, E. S. Ion Mobility Spectrometry: Fundamental Concepts, Instrumentation, Applications, and the Road Ahead. J. Am. Soc. Mass Spectrom. 2019, 30 (11), 2185– 2195,  DOI: 10.1007/s13361-019-02288-2

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    42

    Ion Mobility Spectrometry: Fundamental Concepts, Instrumentation, Applications, and the Road Ahead

    Dodds, James N.; Baker, Erin S.

    Journal of the American Society for Mass Spectrometry (2019), 30 (11), 2185-2195CODEN: JAMSEF; ISSN:1044-0305. (Springer)

    A review. Ion mobility spectrometry (IMS) is a rapid sepn. technique that has experienced exponential growth as a field of study. Interfacing IMS with mass spectrometry (IMS-MS) provides addnl. anal. power as complementary sepns. from each technique enable multidimensional characterization of detected analytes. IMS sepns. occur on a millisecond timescale, and therefore can be readily nested into traditional GC and LC/MS workflows. However, the continual development of novel IMS methods has generated some level of confusion regarding the advantages and disadvantages of each. In this crit. insight, we aim to clarify some common misconceptions for new users in the community pertaining to the fundamental concepts of the various IMS instrumental platforms (i.e., DTIMS, TWIMS, TIMS, FAIMS, and DMA), while addressing the strengths and shortcomings assocd. with each. Common IMS-MS applications are also discussed in this review, such as sepg. isomeric species, performing signal filtering for MS, and incorporating collision cross-section (CCS) values into both targeted and untargeted omics-based workflows as addnl. ion descriptors for chem. annotation. Although many challenges must be addressed by the IMS community before mobility information is collected in a routine fashion, the future is bright with possibilities.

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43. 43

    Scheres, S. H.; Zhang, W.; Falcon, B.; Goedert, M. Cryo-EM Structures of Tau Filaments. Curr. Opin. Struct. Biol. 2020, 64, 17– 25,  DOI: 10.1016/j.sbi.2020.05.011

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    43

    Cryo-EM structures of tau filaments

    Scheres, Sjors H. W.; Zhang, Wenjuan; Falcon, Benjamin; Goedert, Michel

    Current Opinion in Structural Biology (2020), 64 (), 17-25CODEN: COSBEF; ISSN:0959-440X. (Elsevier Ltd.)

    A review. Assembly of microtubule-assocd. protein tau into filamentous inclusions underlies many human neurodegenerative diseases, called tauopathies. Tau inclusions display distinct cellular and neuroanatomical distributions in different tauopathies. Morphol. and biochem. differences suggest that tau filaments adopt disease-specific mol. conformers, similar to prion strains. Breakthroughs in electron cryo-microscopy have recently yielded at. structures of tau filaments extd. from the brains of individuals with various tauopathies. Each disease is characterised by a unique tau filament fold, which is conserved among individuals with the same disease. In vitro aggregation yields different structures from those obsd. in brain. Tau isoform compn., post-translational modifications or interactions with cofactors may det. which structures are formed in brain. Understanding filament formation will be central to deciphering the mol. mechanisms that underlie human tauopathies.

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44. 44

    Bleiholder, C.; Dupuis, N. F.; Wyttenbach, T.; Bowers, M. T. Ion Mobility-Mass Spectrometry Reveals a Conformational Con-Version from Random Assembly to β-Sheet in Amyloid Fibril For-Mation. Nat. Chem. 2011, 3, 172– 177,  DOI: 10.1038/nchem.945

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    44

    Ion mobility-mass spectrometry reveals a conformational conversion from random assembly to β-sheet in amyloid fibril formation

    Bleiholder, Christian; Dupuis, Nicholas F.; Wyttenbach, Thomas; Bowers, Michael T.

    Nature Chemistry (2011), 3 (2), 172-177CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)

    Amyloid cascades that lead to peptide β-sheet fibrils and plaques are central to many important diseases. Recently, intermediate assemblies of these cascades were identified as the toxic agents that interact with cellular machinery. The location and cause of the transformation from a natively unstructured assembly to the β-sheet oligomers found in all fibrils is important in understanding disease onset and the development of therapeutic agents. Largely, research on this early oligomeric region was unsuccessful because all the traditional techniques measure only the av. oligomer properties of the ensemble. We utilized ion-mobility methods to deduce the peptide self-assembly mechanism and examd. a series of amyloid-forming peptides clipped from larger peptides or proteins assocd. with disease. We provide unambiguous evidence for structural transitions in each of these fibril-forming peptide systems and establish the potential of this method for the development of therapeutic agents and drug evaluation.

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45. 45

    Chakraborty, P.; Neumaier, M.; Weis, P.; Kappes, M. M. Exploring Isomerism in Isolated Cyclodextrin Oligomers through Trapped Ion Mobility Mass Spectrometry. J. Am. Soc. Mass Spectrom. 2023, 34 (4), 676– 684,  DOI: 10.1021/jasms.2c00351

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    45

    Exploring Isomerism in Isolated Cyclodextrin Oligomers through Trapped Ion Mobility Mass Spectrometry

    Chakraborty, Papri; Neumaier, Marco; Weis, Patrick; Kappes, Manfred M.

    Journal of the American Society for Mass Spectrometry (2023), 34 (4), 676-684CODEN: JAMSEF; ISSN:1879-1123. (American Chemical Society)

    Cyclodextrin (CD) macrocycles are used to create a wide range of supramol. architectures which are also of interest in applications such as selective gas adsorption, drug delivery, and catalysis. However, predicting their assemblies and identifying the possible isomers in CD oligomers have always remained challenging due to their dynamic nature. Herein, we interacted CDs (α, β, and γ) with a divalent metal ion, Cu2+, to create a series of Cu2+-linked CD oligomers, from dimers to pentamers. We characterized these oligomers using electrospray ionization mass spectrometry and probed isomerism in each of these isolated oligomers using high resoln. trapped ion mobility spectrometry. Using this technique, we sepd. multiple isomers for each of the Cu2+-interlinked CD oligomers and estd. their relative population, which was not accessible previously using other characterization techniques. We further carried out structural anal. of the obsd. isomers by comparing the exptl. collision cross sections (CCSs) to that of modeled structures. We infer that the isomeric heterogeneity reflects size-specific packing patterns of individual CDs (e.g., close-packed/linear). In some cases, we also reveal the existence of kinetically trapped structures in the gas phase and study their transformation to thermodynamically controlled forms by examg. the influence of activation of the ions on isomer interconversion.

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46. 46

    Do, T. D.; de Almeida, N. E. C.; LaPointe, N. E.; Chamas, A.; Feinstein, S. C.; Bowers, M. T. Amino Acid Metaclusters: Implications of Growth Trends on Peptide Self-Assembly and Structure. Anal. Chem. 2016, 88 (1), 868– 876,  DOI: 10.1021/acs.analchem.5b03454

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    46

    Amino Acid Metaclusters: Implications of Growth Trends on Peptide Self-Assembly and Structure

    Do, Thanh D.; de Almeida, Natalia E. C.; LaPointe, Nichole E.; Chamas, Ali; Feinstein, Stuart C.; Bowers, Michael T.

    Analytical Chemistry (Washington, DC, United States) (2016), 88 (1), 868-876CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)

    Ion-mobility mass spectrometry was used to examine the metacluster formation of serine, asparagine, isoleucine, and tryptophan. These amino acids are representative of different classes of noncharged amino acids. They can form relatively large metaclusters in soln. that are difficult or impossible to observe by traditional soln. techniques. The authors further demonstrate, as an example, that the formation of Ser metaclusters is not an ESI artifact because large metaclusters can be detected in neg. polarity and low concn. with similar cross sections to those measured in pos. polarity and higher concn. The growth trends of tryptophan and isoleucine metaclusters, along with serine, asparagine, and the previously studied phenylalanine, are balanced among various intrinsic properties of individual amino acids (e.g., hydrophobicity, size, and shape). The metacluster cross sections of hydrophilic residues (Ser, Asn, Trp) tend to stay on or fall below the isotropic model trend lines, whereas those of hydrophobic amino acids (Ile, Phe) deviate pos. from the isotropic trend lines. The growth trends correlate well to the predicted aggregation propensity of individual amino acids. From the metacluster data, the authors introduce a novel approach to score and predict aggregation propensity of peptides, which can offer a significant improvement over the existing methods in terms of accuracy. Using a set of hexapeptides, the strong neg. deviations of Ser metaclusters from the isotropic model leads a prediction of microcryst. formation for the SFSFSF peptide, whereas the strong pos. deviation of Ile leads to prediction of fibril formation for the NININI peptide. Both predictions are confirmed exptl. using ion mobility and TEM measurements. The peptide SISISI is predicted to only weakly aggregate, a prediction confirmed by TEM.

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47. 47

    Young, L.; Ndlovu, H.; Knapman, T. W.; Harris, S. A.; Radford, S. E.; Ashcroft, A. E. Monitoring Oligomer Formation from Self-Aggregating Amylin Peptides Using ESI-IMS-MS. Int. J. Ion Mobility Spectrom. 2013, 16 (1), 29– 39,  DOI: 10.1007/s12127-012-0115-z

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48. 48

    Matthes, D.; Gapsys, V.; Brennecke, J. T.; de Groot, B. L. An Atomistic View of Amyloidogenic Self-Assembly: Structure and Dynamics of Heterogeneous Conformational States in the Pre-Nucleation Phase. Sci. Rep. 2016, 6 (1), 33156  DOI: 10.1038/srep33156

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49. 49

    Michaels, T. C. T.; Šarić, A.; Curk, S.; Bernfur, K.; Arosio, P.; Meisl, G.; Dear, A. J.; Cohen, S. I. A.; Dobson, C. M.; Vendruscolo, M.; Linse, S.; Knowles, T. P. J. Dynamics of Oligomer Populations Formed during the Aggregation of Alzheimer’s Aβ42 Peptide. Nat. Chem. 2020, 12 (5), 445– 451,  DOI: 10.1038/s41557-020-0452-1

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    Dynamics of oligomer populations formed during the aggregation of Alzheimer's Aβ42 peptide

    Michaels, Thomas C. T.; Saric, Andela; Curk, Samo; Bernfur, Katja; Arosio, Paolo; Meisl, Georg; Dear, Alexander J.; Cohen, Samuel I. A.; Dobson, Christopher M.; Vendruscolo, Michele; Linse, Sara; Knowles, Tuomas P. J.

    Nature Chemistry (2020), 12 (5), 445-451CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)

    Oligomeric species populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer's disease, but the fundamental mol. pathways that control their dynamics have yet to be elucidated. By developing a general approach that combines theory, expt. and simulation, we reveal, in mol. detail, the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we found that most Aβ42 oligomers dissoc. into their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar structures. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to those of aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases.

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50. 50

    Davidson, K. L.; Oberreit, D. R.; Hogan, C. J.; Bush, M. F. Nonspecific Aggregation in Native Electrokinetic Nanoelectrospray Ionization. Int. J. Mass Spectrom. 2017, 420, 35– 42,  DOI: 10.1016/j.ijms.2016.09.013

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    Nonspecific aggregation in native electrokinetic nanoelectrospray ionization

    Davidson, Kimberly L.; Oberreit, Derek R.; Hogan, Christopher J., Jr.; Bush, Matthew F.

    International Journal of Mass Spectrometry (2017), 420 (), 35-42CODEN: IMSPF8; ISSN:1387-3806. (Elsevier B.V.)

    Native mass spectrometry is widely used to det. the stoichiometries and binding consts. of noncovalent interactions in soln. One challenge is that multiple analytes in a single electrospray droplet can aggregate during solvent evapn., which will bias the distribution of oligomeric states obsd. during gas-phase measurements. Here, measurements of soln. flow rates, electrospray currents, droplet size distributions, and nonspecific aggregation are used in conjunction with Poisson statistics to characterize the factors that control nonspecific aggregation during typical native mass spectrometry expts. Using electrokinetic nanoelectrospray ionization and a 30 nA current, low flow rates of less than 10 nL min-1 and initial droplets with mean diams. of ∼60 nm were obsd. For solns. contg. 4μM analyte under these conditions, Poisson statistics and charge-redn. drift tube ion mobility spectrometry both indicate that ∼90% of the desolvated, occupied droplets contain a single analyte. Initial droplet sizes and contributions from nonspecific aggregates both increase with increasing current. Ion mobility mass spectrometry anal. of the ions produced using these conditions without charge redn. exhibit even less nonspecific aggregation (∼2%). All approaches indicate that increasing the ionization current increases the flow rate, droplet size distribution, and extent of nonspecific aggregation.

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51. 51

    Jordan, J. S.; Williams, E. R. Effects of Electrospray Droplet Size on Analyte Aggregation: Evidence for Serine Octamer in Solution. Anal. Chem. 2021, 93 (3), 1725– 1731,  DOI: 10.1021/acs.analchem.0c04343

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    51

    Effects of Electrospray Droplet Size on Analyte Aggregation: Evidence for Serine Octamer in Solution

    Jordan, Jacob S.; Williams, Evan R.

    Analytical Chemistry (Washington, DC, United States) (2021), 93 (3), 1725-1731CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)

    Spraying solns. of serine under a wide variety of conditions results in unusually abundant gaseous octamer clusters that exhibit significant homochiral specificity, but the extent to which these clusters exist in soln. or are formed by clustering during droplet evapn. has been debated. Electrospray ionization emitters with tip sizes between 210 nm and 9.2μm were used to constrain the no. of serine mols. that droplets initially contain. Protonated octamer was obsd. for all tip sizes with 10 mM serine soln., but the abundance decreases from 10% of the serine population at the largest tip size to ~ 5.6% for the two smallest tip sizes. At 100μM, the population abundance of the protonated serine octamer decreases from 1% to 0.6% from the largest to the smallest tip size, resp. At 100μM, fewer than 10% of the initial droplets should contain even a single analyte mol. with 210 nm emitter tips. These results indicate that the majority of protonated octamer obsd. in mass spectra under previous conditions is formed by clustering inside the electrospray droplet, but ≤5.6% and ~ 0.6% of serine exists as an octamer complex in 10 mM and 100μM solns., resp. These results show that aggregation occurs in large droplets, but this aggregation can be eliminated using emitters with sufficiently small tips. Use of these emitters with small tips is advantageous for clearly distinguishing between species that exist in soln. and species formed by clustering inside droplets as solvent evapn. occurs.

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52. 52

    Laos, V.; Do, T. D.; Bishop, D.; Jin, Y.; Marsh, N. M.; Quon, B.; Fetters, M.; Cantrell, K. L.; Buratto, S. K.; Bowers, M. T. Characterizing TDP-43307–319 Oligomeric Assembly: Mechanistic and Structural Implications Involved in the Etiology of Amyotrophic Lateral Sclerosis. ACS Chem. Neurosci. 2019, 10 (9), 4112– 4123,  DOI: 10.1021/acschemneuro.9b00337

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    52

    Characterizing TDP-43307-319 Oligomeric Assembly: Mechanistic and Structural Implications Involved in the Etiology of Amyotrophic Lateral Sclerosis

    Laos, Veronica; Do, Thanh D.; Bishop, Dezmond; Jin, Yingying; Marsh, Nicole M.; Quon, Brady; Fetters, Megan; Cantrell, Kristi Lazar; Buratto, Steven K.; Bowers, Michael T.

    ACS Chemical Neuroscience (2019), 10 (9), 4112-4123CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)

    Aggregation of TAR DNA-binding protein of 43kDa (TDP-43) is a salient feature for amyotrophic lateral sclerosis (ALS), a debilitating neurodegenerative disorder affecting over 200,000 people worldwide. The protein undergoes both functional and pathogenic aggregation; the latter is irreversible and hypothesized to produce sol. oligomers that are toxic to neurons in addn. to inclusions made of stable fibrous deposits. Despite progress made towards identifying disease-related proteins, the underlying pathogenic mechanism assocd. with these toxic oligomers remains elusive. Utilizing a multimodal approach which combines several measurement techniques (CD, Thioflavin T spec-troscopy (ThT), Fourier transform IR spectroscopy (FTIR)), high spatial resoln. imaging tools (electron microscopy (EM) and at. force microscopy (AFM)), with soft ion mobility mass spectrometry (IM-MS) and atomistic mol. dynamics (MD) simulations, we explore the oligomerization mechanisms, structures and assembly pathways of TDP-43(307-319). This fragment is both amyloidogenic and toxic and is within the glycine rich C-terminal domain essential for both toxicity and aggregation of the full-length protein. In addn. to the wild-type peptide, two ALS-related mutants (A315T and A315E), and a non-axon toxic mutant (G314V), were investigated to det. how mutations affect the oligomerization of TDP-43(307-319) and structures of toxic oligomers. The results of our study provides new insights into how ALS-related mutants, A315T and A315E, accelerate and/or alter the pathogenic mechanism and highlight the role of an internal glycine, G314, in maintaining efficient packing known to be crit. for functional oligomer assembly. More importantly, our data demonstrate that G314 plays a vital role in TDP-43 assembly and prevents cytotoxicity via its unique aversion to oligomers larger than trimer. Our observation is consistent with previous studies showing that G314V mutation of the full-length TDP-43 induced remediation of both axonotoxicity and neuronal apoptosis. Our findings reveal a distinct aggregation mechanism for each peptide, and elucidate oligomeric species and possible structures that may be involved in the pathol. of ALS.

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53. 53

    Österlund, N.; Moons, R.; Ilag, L. L.; Sobott, F.; Gräslund, A. Native Ion Mobility-Mass Spectrometry Reveals the Formation of β-Barrel Shaped Amyloid-β Hexamers in a Membrane-Mimicking Environment. J. Am. Chem. Soc. 2019, 141 (26), 10440– 10450,  DOI: 10.1021/jacs.9b04596

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    53

    Native Ion Mobility-Mass Spectrometry Reveals the Formation of β-Barrel Shaped Amyloid-β Hexamers in a Membrane-Mimicking Environment

    Osterlund Nicklas; Graslund Astrid; Moons Rani; Sobott Frank; Ilag Leopold L; Sobott Frank; Sobott Frank

    Journal of the American Chemical Society (2019), 141 (26), 10440-10450 ISSN:.

    The mechanisms behind the Amyloid-β (Aβ) peptide neurotoxicity in Alzheimer's disease are intensely studied and under debate. One suggested mechanism is that the peptides assemble in biological membranes to form β-barrel shaped oligomeric pores that induce cell leakage. Direct detection of such putative assemblies and their exact oligomeric states is however complicated by a high level of heterogeneity. The theory consequently remains controversial, and the actual formation of pore structures is disputed. We herein overcome the heterogeneity problem by employing a native mass spectrometry approach and demonstrate that Aβ(1-42) peptides form coclusters with membrane mimetic detergent micelles. The coclusters are gently ionized using nanoelectrospray and transferred into the mass spectrometer where the detergent molecules are stripped away using collisional activation. We show that Aβ(1-42) indeed oligomerizes over time in the micellar environment, forming hexamers with collision cross sections in agreement with a general β-barrel structure. We also show that such oligomers are maintained and even stabilized by addition of lipids. Aβ(1-40) on the other hand form significantly lower amounts of oligomers, which are also of lower oligomeric state compared to Aβ(1-42) oligomers. Our results thus support the oligomeric pore hypothesis as one important cell toxicity mechanism in Alzheimer's disease. The presented native mass spectrometry approach is a promising way to study such potentially very neurotoxic species and how they could be stabilized or destabilized by molecules of cellular or therapeutic relevance.

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54. 54

    Bakels, S.; Daly, S.; Doğan, B.; Baerenfaenger, M.; Commandeur, J.; Rijs, A. Probing High-Order Transient Oligomers Using Ion Mobility Mass Spectrometry Coupled to Infrared Action Spectroscopy. Anal. Chem. 2024, 96 (34), 13962– 13970,  DOI: 10.1021/acs.analchem.4c02749

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55. 55

    Ridgeway, M. E.; Lubeck, M.; Jordens, J.; Mann, M.; Park, M. A. Trapped Ion Mobility Spectrometry: A Short Review. Int. J. Mass Spectrom. 2018, 425, 22– 35,  DOI: 10.1016/j.ijms.2018.01.006

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    55

    Trapped ion mobility spectrometry: A short review

    Ridgeway, Mark E.; Lubeck, Markus; Jordens, Jan; Mann, Mattias; Park, Melvin A.

    International Journal of Mass Spectrometry (2018), 425 (), 22-35CODEN: IMSPF8; ISSN:1387-3806. (Elsevier B.V.)

    Trapped ion mobility spectrometry (TIMS) hybridized with mass spectrometry (MS) is a relatively recent advance in the field of ion mobility mass spectrometry (IMMS). The basic idea behind TIMS is the reversal of the classic drift cell analyzer. Rather than driving ions through a stationary gas, as in a drift cell, TIMS holds the ions stationary in a moving column of gas. This has the immediate advantage that the phys. dimension of the analyzer can be small (∼5 cm) whereas the anal. column of gas - the column that flows past during the course of an anal. - can be large (as much as 10 m) and user defined. In the years since the first publication, TIMS has proven to be a highly versatile alternative to drift tube ion mobility achieving high resolving power (R ∼ 300), duty cycle (100%), and efficiency (∼80%). In addn. to its basic performance specifications, the flexibility of TIMS allows it to be adapted to a variety of applications. This is highlighted particularly by the PASEF (parallel accumulation serial fragmentation) workflow, which adapts TIMS-MS to the shotgun proteomics application. In this brief review, the general operating principles, theory, and a no. of TIMS-MS applications are summarized.

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56. 56

    Silveira, J. A.; Michelmann, K.; Ridgeway, M. E.; Park, M. A. Fundamentals of Trapped Ion Mobility Spectrometry Part II: Fluid Dynamics. J. Am. Soc. Mass Spectrom. 2016, 27 (4), 585– 595,  DOI: 10.1007/s13361-015-1310-z

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    56

    Fundamentals of Trapped Ion Mobility Spectrometry Part II: Fluid Dynamics

    Silveira, Joshua A.; Michelmann, Karsten; Ridgeway, Mark E.; Park, Melvin A.

    Journal of the American Society for Mass Spectrometry (2016), 27 (4), 585-595CODEN: JAMSEF; ISSN:1044-0305. (Springer)

    Trapped ion mobility spectrometry (TIMS) is a high resoln. (R up to ∼300) sepn. technique which uses an elec. field to hold ions stationary against a moving gas. Recently, an anal. model for TIMS was derived and, in part, exptl. verified. A central, but not yet fully explored, model component involves fluid dynamics at work. This work characterized fluid dynamics in TIMS using simulations and ion mobility expts. Results indicated subsonic laminar flow develops in the analyzer, with pressure-dependent gas velocities from ∼120 to 170 m/s measured at the ion elution position. A key philosophical question is: how can mobility be measured in a dynamic system where the gas is expanding and its velocity is changing. The authors previously noted that anal. useful work is primarily done on ions as they traverse the elec. field gradient plateau in the analyzer. This work showed the position-dependent change in gas velocity on the plateau is balanced by a change in pressure and temp., ultimately resulting in a near, position-independent drag force. Since the drag force and related variables are nearly const., they allow for the use of relatively simple equations to describe TIMS behavior. Nonetheless, a more comprehensive model, which accounts for the spatial dependence of flow variables, was derived. Exptl. resolving power trends closely agreed with the theor. dependence of the drag force, thereby validating another principal component of TIMS theory.

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57. 57

    Hernandez, D. R.; DeBord, J. D.; Ridgeway, M. E.; Kaplan, D. A.; Park, M. A.; Fernandez-Lima, F. Ion Dynamics in a Trapped Ion Mobility Spectrometer. Analyst 2014, 139 (8), 1913– 1921,  DOI: 10.1039/C3AN02174B

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    57

    Ion dynamics in a trapped ion mobility spectrometer

    Hernandez, Diana Rosa; DeBord, John Daniel; Ridgeway, Mark E.; Kaplan, Desmond A.; Park, Melvin A.; Fernandez-Lima, Francisco

    Analyst (Cambridge, United Kingdom) (2014), 139 (8), 1913-1921CODEN: ANALAO; ISSN:0003-2654. (Royal Society of Chemistry)

    Theor. simulations and exptl. observations are used to describe the ion dynamics in a trapped ion mobility spectrometer. In particular, the ion motion, ion transmission and mobility sepn. are discussed as a function of the bath gas velocity, radial confinement, anal. time and speed. Mobility anal. and calibration procedure are reported for the case of sphere-like mols. for pos. and neg. ion modes. A maximal mobility resoln. can be achieved by optimizing the gas velocity, radial confinement (RF amplitude) and ramp speed (voltage range and ramp time). The mobility resoln. scales with the elec. field and gas velocity and R = 100-250 can be routinely obtained at room temp.

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    Silveira, J. A.; Ridgeway, M. E.; Park, M. A. High Resolution Trapped Ion Mobility Spectrometery of Peptides. Anal. Chem. 2014, 86 (12), 5624– 5627,  DOI: 10.1021/ac501261h

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    58

    High Resolution Trapped Ion Mobility Spectrometry of Peptides

    Silveira, Joshua A.; Ridgeway, Mark E.; Park, Melvin A.

    Analytical Chemistry (Washington, DC, United States) (2014), 86 (12), 5624-5627CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)

    The authors employ trapped ion mobility spectrometry (TIMS) for conformational anal. of several model peptides. The TIMS distributions are extensively compared to recent ion mobility spectrometry (IMS) studies reported in the literature. At a resolving power (R) exceeding 250, many new features, otherwise hidden by lower resoln. IMS analyzers, are revealed. Though still principally limited by the plurality of conformational states, at present, TIMS offers R up to ∼3 to 8 times greater than modern drift tube or traveling wave IMS techniques, resp. Unlike differential IMS, TIMS not only is able to resolve congested conformational features but also can be used to det. information about their relative size, via the ion-neutral collision cross section, offering a powerful new platform to probe the structure and dynamics of biochem. systems in the gas phase.

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59. 59

    Götze, M.; Polewski, L.; Bechtella, L.; Pagel, K. A 3D-Printed Offline Nano-ESI Source for Bruker MS Instruments. J. Am. Soc. Mass Spectrom. 2023, 34 (10), 2403– 2406,  DOI: 10.1021/jasms.3c00214

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    Depraz Depland, A.; Stroganova, I.; Wootton, C. A.; Rijs, A. M. Developments in Trapped Ion Mobility Mass Spectrometry to Probe the Early Stages of Peptide Aggregation. J. Am. Soc. Mass Spectrom. 2023, 34 (2), 193– 204,  DOI: 10.1021/jasms.2c00253

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    60

    Developments in Trapped Ion Mobility Mass Spectrometry to Probe the Early Stages of Peptide Aggregation

    Depraz Depland, Agathe; Stroganova, Iuliia; Wootton, Christopher A.; Rijs, Anouk M.

    Journal of the American Society for Mass Spectrometry (2023), 34 (2), 193-204CODEN: JAMSEF; ISSN:1879-1123. (American Chemical Society)

    Ion mobility mass spectrometry (IM-MS) has proven to be an excellent method to characterize the structure of amyloidogenic protein and peptide aggregates, which are formed in coincidence with the development of neurodegenerative diseases. However, it remains a challenge to obtain detailed structural information on all conformational intermediates, originating from the early onset of those pathologies, due to their complex and heterogeneous environment. One way to enhance the insights and the identification of these early stage oligomers is by employing high resoln. ion mobility mass spectrometry expts. This would allow us to enhance the mobility sepn. and MS characterization. Trapped ion mobility spectrometry (TIMS) is an ion mobility technique known for its inherently high resoln. and has successfully been applied to the anal. of protein conformations among others. To obtain conformational information on fragile peptide aggregates, the instrumental parameters of the TIMS-Quadrupole-Time-of-Flight mass spectrometer (TIMS-qToF-MS) have to be optimized to allow the study of intact aggregates and ensure their transmission toward the detector. Here, we investigate the suitability and application of TIMS to probe the aggregation process, targeting the well-characterized M307-N319 peptide segment of the TDP-43 protein, which is involved in the development of amyotrophic lateral sclerosis. By studying the influence of key parameters over the full mass spectrometer, such as source temp., applied voltages or RFs among others, we demonstrate that by using an optimized instrumental method TIMS can be used to probe peptide aggregation.

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