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Physiological and Pathological Roles of Cdk5: Potential Directions for Therapeutic Targeting in Neurodegenerative Disease

  • Annamarie B. Allnutt
    Annamarie B. Allnutt
    Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health Center, Santa Monica, California 90404, United States
  • Ariana K. Waters
    Ariana K. Waters
    Drug Discovery and Nanomedicine Laboratory, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health Center, Santa Monica, California 90404, United States
  • Santosh Kesari
    Santosh Kesari
    Translational Neurosciences and Neurotherapeutics, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health Center, Santa Monica, California 90404, United States
  • , and 
  • Venkata Mahidhar Yenugonda*
    Venkata Mahidhar Yenugonda
    Drug Discovery and Nanomedicine Laboratory, John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health Center, Santa Monica, California 90404, United States
    *Phone: +001-3105827489. Email: [email protected]
Cite this: ACS Chem. Neurosci. 2020, 11, 9, 1218–1230
Publication Date (Web):April 14, 2020
https://doi.org/10.1021/acschemneuro.0c00096

Copyright © 2020 American Chemical Society. This publication is licensed under these Terms of Use.

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Abstract

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine (ser)/threonine (Thr) kinase that has been demonstrated to be one of the most functionally diverse kinases within neurons. Cdk5 is regulated via binding with its neuron-specific regulatory subunits, p35 or p39. Cdk5–p35 activity is critical for a variety of developmental and cellular processes in the brain, including neuron migration, memory formation, microtubule regulation, and cell cycle suppression. Aberrant activation of Cdk5 via the truncated p35 byproduct, p25, is implicated in the pathogenesis of several neurodegenerative diseases. The present review highlights the importance of Cdk5 activity and function in the brain and demonstrates how deregulation of Cdk5 can contribute to the development of neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease. Additionally, we cover past drug discovery attempts at inhibiting Cdk5–p25 activity and discuss which types of targeting strategies may prove to be the most successful moving forward.

1. Introduction

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Cyclin dependent kinases (Cdks) are serine/threonine protein kinases that are highly expressed in proliferating cells. The Cdk family consists of 20 serine/threonine protein kinases that are primarily involved in the regulation of cell cycle events, gene transcription and cell differentiation. (1,2) Cdks 1, 2, 4, and 6 regulate the cell cycle, whereas Cdks 7, 8, 9, 12, and 13 regulate transcription. The other Cdks, including Cdk5, have unique and often tissue-dependent functions. The first Cdk, discovered through biochemical and genetic studies in yeast, was initially named cell division cycle 2 (Cdc2) due to its structural similarity to a yeast fission kinase of the same name. (3) This kinase was later termed cyclin dependent kinase 1 (Cdk1) after it was confirmed that activation of this kinase was dependent on association with cyclin subunits. (3) The majority of Cdks are reliant on association with one or more cyclins for enzymatic activity and require phosphorylation in the activation segment (or T-loop) for maximal activation. (2,4)
Cdk5, a cyclin dependent kinase first identified in 1992, (5−7) is often referred to as an atypical member of the mammalian Cdk family. While other Cdks are primarily found in proliferating cells, Cdk5 is predominantly located in postmitotic neurons where it plays a vital role in brain development, neuronal survival, synaptic plasticity, microtubule regulation, and pain signaling. (8,9) Unlike other Cdks, Cdk5 plays a minimal role in directing cell cycle events; however, when dysregulated, Cdk5 can initiate cell cycle reentry in postmitotic neurons, leading to neuronal cell death. (10−12) Additionally, while Cdk5 has high sequence homology to the other Cdks in its primary sequence, it is not reliant on cyclins or phosphorylation in the T-loop for activation. (13) Rather, Cdk5 is activated by binding to its neural-specific regulatory proteins, p35 and p39, that are structurally similar to cyclins but share no homology on the amino acid level. (13)
Cdk5 dysregulation can mainly be attributed to its activation by the N-terminal truncated isoform of p35, p25, which results in hyperactivation of Cdk5 and aberrant subcellular localization, changes that have disastrous consequences for the health of neurons. (8,14) Cdk5 dysregulation has been strongly implicated in the progression of synaptic dysfunction and neuronal death in neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Cdk5 was first recognized in relation to neurodegeneration in the early 1990s, when it was discovered that Cdk5 was capable of producing the aberrantly phosphorylated tau seen in AD. (14) Since then, Cdk5 has been at the center of Alzheimer’s research and has been shown to contribute to the formation of neuronal plaques and neurofibrillary tangles (8,15) as well to the development of other pathological events such as mitochondria dysfunction, (16) nuclear envelope dispersion, (17) and Golgi fragmentation. (18) Cdk5 first became implicated in Parkinson’s disease when it was found that elevated Cdk5 and p25 correlated with degeneration of dopaminergic neurons in the substantia nigra. (19) Interestingly, Cdk5–p35 activity is associated with reduced neurotoxicity in Huntington’s disease (HD). (20)
Although dysregulation of Cdk5 is associated chiefly with instigating neurodegeneration, the kinase itself is ubiquitously expressed and plays pathological roles in non-neuronal tissues as well, (21) ncluding in multiple types of solid and hematological malignancies. (22) The multifaceted role of Cdk5 in causing disease has made it an attractive target for therapeutic intervention. However, there have been no successful small molecule candidates reported to date that selectively inhibit Cdk5 kinase activity. This present review highlights some of the major physiological functions of Cdk5 as well as the ways that its dysregulation contributes to neurodegenerative diseases. We address some of the challenges with targeting Cdk5 therapeutically and discuss possible drug discovery strategies to inhibit pathological Cdk5 activity which may open new therapeutic avenues to accomplish disease modification.

2. Structure and Regulation of Cdk5

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Cdk5 is a proline-directed cyclin dependent kinase that has high sequence homology to the other Cdks in its primary sequence. (9,23−25) Cdks are typically activated by binding with specific cyclins and require phosphorylation in the activation segment (or T-loop) for maximal activation. The structure of unbound Cdk2, the Cdk most structurally similar to Cdk5, displays a folded activation segment with a covered substrate-binding pocket, precluding catalytic activity. Upon binding the cyclin-box fold (CBF) of cyclin-A, Cdk2 undergoes a conformational change, revealing the activation segment allowing for its phosphorylation by Cdk activating kinase (CAK) at threonine residue 160 (Thr160). (13) This phosphorylation stabilizes the conformation, provides substrate-specificity, and dramatically increases substrate binding affinity and catalytic rate. (26)
By contrast, Cdk5 is not dependent on association with cyclins or phosphorylation for maximal activation. Cdk5 is activated instead by binding to its neural-specific regulatory proteins p35 and p39 (26,27) and their corresponding proteolytic products p25 and p29, respectively, as they retain the two C-terminal helices (α6 and α7) that are directly implicated in binding Cdk5. (26,28) p35 and p25 share no homology to cyclins on the amino acid level. However, structural analysis of the Cdk5–p25 and Cdk5–p35 complexes reveals that Cdk5’s activators form a tertiary structure similar to the CBF domain that characterizes cyclins. (13) This CBF-like domain of p25 and p35 makes extensive contacts with the T-loop, stabilizing the T-loop in an active conformation such that phosphorylation is not necessary for further activation. In fact, the active conformation of Cdk5–p25 is indistinguishable from the active conformation of phosphorylated Cdk2. (13) p35 and p39, as well as their proteolytic products, are predominantly expressed in postmitotic neurons. Consequently, the highest level of Cdk5 activity is found in neurons. (29,30) An abundance of Cdk5 relative to p35 and p39 in neurons indicates that the levels of these protein activators are the limiting factor for Cdk5 kinase activity. (31,32) Therefore, regulation of Cdk5 activity is predominantly achieved through tight regulation of the synthesis and degradation of its activators. Synthesis of p35 can be stimulated by nerve-growth factor (NGF) or brain-derived neutrophic factor (BDNF) along with extracellular matrix molecules. (30) Degradation of p35 occurs rapidly due to its N-terminal p10 region containing the signal for ubiquitin-mediated proteolysis. (15) Degradation of p35 can also be initiated through its own phosphorylation by Cdk5, a mechanism by which Cdk5 autoinhibits its activity (Figure 1A). (33) While phosphorylation is not required for activation of Cdk5, its kinase activity and substrate specificity are, in part, regulated by phosphorylation. Cdk5 is phosphorylated at three main sites: Thr14, Tyr15, and Ser159. (34) Phosphorylation at Thr14 results in inhibition of Cdk5, while phosphorylation at Ser159 leads to increased Cdk5 activation. (35,36)

Figure 1

Figure 1. (A) Physiological condition: Cdk5 is chiefly activated by p35. Due to the ubiquitination signal held by the p10 fragment of p35, the Cdk5–p35 complex has a short half-life and is rapidly degraded by the proteasome. Cdk5 also autoinhibits its activity by phosphorylating and subsequently degrading p35. Cdk5 activity is limited to membrane targeting due to the myristoylation sequence present in the p10 fragment. (B) Pathological condition: Under pathological conditions, neurotoxic stimuli increase intracellular calcium levels that leads to the activation of calpain, a protease which cleaves the p10 fragment from p35 to produce p25. Losing the p10 fragment’s ubiquitination signal results in a significantly longer half-life for the Cdk5–p25 complex, leading to hyperactivation of Cdk5 and hyperphosphorylation of its physiological targets. Additionally, losing the myristoylation sequence allows Cdk5–p25 to relocate to the nucleus where it phosphorylates nonphysiological targets.

Dysregulation of Cdk5 is, in large part, attributed to the formation and accumulation of the neurotoxic derivatives of p35 and p39, namely, p25 and p29. (14) When the N-terminal p10 region is cleaved from p35/p39 by calpains, a group of Ca2+ activated cytosolic proteases, the ubiquitination signal is lost. The resultant p25 and p29 fragments are more stable with a 5–10-fold greater half-life compared to p35/p39. Consequently, this leads to hyperactivation of Cdk5. (14) The p10 fragment plays another important role in Cdk5 regulation as it contains the myristoylation signal that limits active Cdk5 targeting to the membrane. (37) When the myristoylation signal is lost, the subcellular localization of the Cdk5–p25 complex changes, with nonmyristoylated p35/p39 preferentially accumulating in the nucleus. (37) The mis-localization of the Cdk5–p25 complex then allows for phosphorylation of nonphysiological targets such as peroxiredoxin 1 and 2 (Prx1/2), lamin A and B1, and Cdc24A, Cdc25B, and Cdc25c. These aberrant phosphorylation events result in neurotoxicity and neuronal death (Figure 1B). (12,17,18)

3. Role of Cdk5 Activity in CNS Development

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3.1. Brain Development

Knockout studies have demonstrated that both Cdk5 and its activators are essential for proper neurodevelopment and viability. Mice deficient in Cdk5 (Cdk5 −/−) die perinatally and exhibit numerous abnormalities in the cerebral cortex, hippocampus and cerebellum. (38) These mice display an inverted pattern of laminar organization of neurons in the cerebral cortex, the pyramidal neurons of the hippocampus are not organized in a discrete layer, and the cerebellum lacks obvious foliation. (38−40) Mice lacking both p35 and p39 display similar patterns of neural disruption and also die perinatally, making them indistinguishable from the Cdk5 −/– mutants. (41) These findings indicate that p35 and p39 are the principal activators of Cdk5 and that their role in activating Cdk5 during brain development cannot be replaced by other regulatory proteins.

3.2. Cortical Neuron Migration

Cdk5 plays an integral role in cortical development, as evidenced by the aforementioned knockout studies. Cdk5 is essential in establishing the proper pattern of cortical lamination due to its facilitation of cortical neuron migration. The normal mammalian cerebral cortex consists of six distinct layers arranged in a birth order dependent fashion exhibiting what is typically referred to as a classical “inside-out” pattern. To establish this pattern, freshly postmitotic neurons exiting the ventricular zone (VZ) use radial migration to travel past the subplate and past any preceding layers in the cortical plate (CP) (layers II–VI) to deposit below the superficial marginal zone (MZ) (layer I) and establish a new layer (Figure 2A). In order for radial migration of the newly born neurons to occur, the neurons must undergo a series of morphology changes. (42−44) After neurons complete their final division and exit the VZ, they undergo a multipolar to bipolar transition in the subventricular zone-intermediate zone (SVZ-IZ). This bipolar shape, consisting of a pia-directed leading process and a trailing axon, allows for the locomotion of the entire cell along the radially extending glial fibers present within the cortex. After the locomoting neurons reach the MZ, the neurons transform again and adopt a terminal translocation mode. After this final transformation, dendrite maturation begins.

Figure 2

Figure 2. (A) For the postmitotic cells in the SVZ to begin radial migration along the glial fibers distributed throughout the cortex, they must first adopt a bipolar configuration. Cdk5 is required for the multipolar to bipolar transition and is responsible for the formation of the leading process. As each new cohort of neurons migrates, it must slide past the subplate and past previously deposited cell layers to reach its destination below the MZ. Cdk5–p35 facilitates this process by forming a complex with β-catenin, and subsequently with N-cadherin, to decrease N-cadherin mediated cell–cell adhesion. (B) PCs in the cerebellum primarily display radial migration to reach their final location in the PCL, while GCPs use tangential migration to reach their initial destination in the EGL. Cdk5 is required for the correct migration for both of these cell types, and PCs and GCPs lacking Cdk5 are located ectopically. The final inward migration of GCPs into the IGL is also reliant on Cdk5, and GCPs lacking Cdk5 remain in the EGL.

The proper maturation and migration of the cortical neurons is largely facilitated by Cdk5. In the earliest phase of migration, Cdk5 regulates multipolar cell morphology and is responsible for the formation of the leading process. (45) In these ways, Cdk5 is required for the multipolar to bipolar transition needed for locomotion. (46,47) After the cells adopt a bipolar configuration, they must travel through multiple pre-existing layers of neurons in the CP to reach their own layer, a process assisted by Cdk5. (47,48) Cdk5 associates with β-catenin, which forms a complex with N-cadherin (Ncad), to reduce cadherin-mediated cell–cell adhesion, allowing migrating neurons to slide past preceding layers in the CP. (49,50) Additionally, Cdk5 facilitates nucleokinesis, the translocation of the nucleus, through regulation of microtubule dynamics. (51) In Cdk5 −/– mice, the multipolar-bipolar transition is perturbed and radial migration is strongly arrested. (46,49,50) As a result of these disruptions, Cdk5 −/– mutants exhibit a roughly inverted pattern of cortical lamination. (52) The first population of neurons, future layer VI, appears to be unaffected and migrates correctly past the subplate cells. However, subsequent layers fail to migrate correctly and deposit below the subplate rather than migrating through the CP and depositing below the MZ. Mice lacking p35 display the same pattern of cortical abnormalities suggesting a vital role of Cdk5 and p35 in proper cortical development.

3.3. Cerebellar Development

Cdk5 plays an essential role in the migration of the Purkinje cells (PCs) and granule cell precursors (GCPs) in the developing cerebellum. PCs originate in the VZ of the fourth ventricle, and primarily use radial migration to reach their intended destination in the Purkinje cell layer (PCL), which is above the internal granule layer (IGL) and below both the molecule layer (ML) and the outermost external granule layer (EGL) (Figure 2B). The EGL of the cerebellum is formed by tangentially migrating GCPs originating in the rhombic lip. (53) Mediated by Sonic hedgehog (Shh) secretions from the underlying Purkinje cells, GCPs rapidly proliferate in the EGL until around the second postnatal week. (54) Once cell division ceases, the granule cells migrate into the IGL where they mature, leaving the EGL to eventually disappear. (55,56)
Proper migration of PCs and GCPs in the developing cerebellum requires Cdk5. In chimeric (Cdk5 −/– ↔ Cdk5 +/+) mice, migration of both cell types is affected in a cell-autonomous manner. (39) Cdk5 positive cells are found in their expected locations, whereas Cdk5 deficient cells are located ectopically. Mutant PCs are found deep in the cerebellum rather than in the PCL, and mutant GCPs are found in the ML rather than in the IGL. Midbrain-hindbrain specific Cdk5 conditional knockout (MHB-Cdk5 KO) mice demonstrate these same migration defects. (57) The failure of the GCPs to properly migrate from the EGL into the IGL indicates that Cdk5 plays a role in the inward radial migration of these cells. Additionally, Cdk5 appears to influence the dendritic branching of PCs in a cell non-autonomous manner, as MHB-Cdk5 KO mice display abnormal dendrite morphology in both Cdk5-positve and Cdk5-negative PCs. (57) The cerebellum of MHB-Cdk5 KO mice is significantly smaller and lacks obvious foliation, which accords with the decrease in GCP proliferation seen in these mutant mice. Given that GCP proliferation is reliant on Shh signaling from the underlying PCs, (54) the compromised PCL may be responsible for the loss of volume and foliation.

4. Molecular and Cellular Functions of Cdk5 in the Brain

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4.1. Microtubule Regulation

Microtubules (MTs), consisting of α/β-tubulin heterodimers, are centrally involved in several cellular events including formation of axonal and dendritic processes, intracellular transport, and morphological transitions. MTs are capable of rapidly polymerizing or disassembling, which allows for efficient and extensive reorganization of the cytoskeleton. This defining feature of MTs is essential to neuronal migration and neuroplasticity in the developing brain as well as for the maintenance of the neuronal architecture in the adult brain. (58) MT dynamics are regulated by microtubule associated proteins (MAPs) that directly interact with MTs to either stabilize or destabilize the MT, resulting in increased polymerization or disassembly, respectively.
Cdk5 acts as a mediator of MT dynamics by phosphorylating MAPs to either increase or decrease their association with MTs. By modulating the MAPs’ ability to bind and direct the polymerization activity of MTs, Cdk5 influences the assembly and disassembly of the microtubule network. Through phosphorylation of MAPs such as stathmin, glycogen synthase kinase 3 beta (GSK3β), axin, MAP1B, and tau, Cdk5 promotes axonal elongation. (59) By contrast, phosphorylation and subsequent inhibition of CRMP2 initiates growth cone collapse. (60) When Cdk5 becomes dysregulated, aberrant hyperphosphorylation of MAPs such as tau or CRMP2 contributes to the formation of the neurofibrillary tangles characteristic of Alzheimer’s disease and other neurodegenerative conditions. For a comprehensive review regarding Cdk5 and MT interactions, the reader is directed to the following publication: ref (59).

4.2. Synaptic Plasticity

Cdk5 plays a somewhat controversial role in regard to synaptic plasticity. Numerous studies suggest different and sometimes seemingly conflicting roles for Cdk5 and its effect on learning and memory. (61−65) A negative role for Cdk5 is suggested as a result of its interaction with the NR2B subunit of NMDA receptors. (61) NMDA receptors (NMDARs) are essential in the processes of hippocampal dependent learning and memory. The NR2B subunit of NMDAR is specifically associated with improved synaptic plasticity in conditions where it is highly expressed. (66,67) Plattner et al. showed that Cdk5 acts as a negative regulator of NR2B expression by phosphorylating NR2B at serine 1116. (61) This phosphorylation prevents cell surface expression of NR2B-containing NMDAR and thus attenuates synaptic transmission. Disruption of the interaction between Cdk5 and NR2B by small interfering peptides (SiPs) reduces NR2B phosphorylation, which accords with enhanced learning and memory. (61) Additionally, Hawasli et. al demonstrated that Cdk5 conditional knockout mice display enhanced long-term potentiation (LTP) and synaptic plasticity as a result of decreased Cdk5 and calpain mediated NR2B degradation, further substantiating the role of Cdk5 as a negative regulator of NR2B. Conversely, Cdk5 enhances LTP following direct phosphorylation of the NR2A subunit of NMDAR, an event that increases NMDAR activity. (62) In this context Cdk5 inhibition reduces LTP formation in hippocampal neurons, rather than facilitates it. Interestingly, a study by Fischer et al. indicated that increased Cdk5 activation by p25 enhances LTP and facilitates hippocampal-dependent learning. (63) However, this enhancement was transient, and after prolonged expression of p25, LTP formation reduced dramatically and neuronal loss was observed. This finding suggests that it is the prolonged dysregulation of Cdk5 by p25 that results in the pathological effects of Cdk5 on LTP. Overall, it appears that the role Cdk5 plays in regulating synaptic plasticity is complex and requires further investigation to clarify the significance of its involvement.

4.3. Neuronal Cell Cycle Events

Although referred to as an atypical kinase due to its supposed minimal role in directing cell cycle events, Cdk5 does play an important role in suppressing cell-cycle re-entry of postmitotic neurons. After neurons have terminally differentiated, they enter into a quiescent state. When neurons are exposed to acute insults such as DNA damage or oxidative stress they attempt to re-enter the cell cycle, a process that acts as a signal to trigger neuronal apoptosis. (68) This has been shown to occur in several neurodegenerative diseases. (69−71) Nuclear Cdk5 has been shown to suppress the neuronal cell cycle mechanistically through its disruption of the E2F1–DP1 complex, the formation of which is necessary for cell cycle initiation in most dividing cells. (10) Cdk5 acts to sequester E2F1 from DP1 by forming a three-protein complex involving Cdk5, p35, and E2F1. The formation of this sequestering complex, and its subsequent cell-cycle suppressing activity, is dependent on Cdk5–p35 and neither p25 nor p39 can serve as functional substitutes. (10)
The Cdk5–p25 complex plays a more instigative role in cell cycle re-entry by promoting DNA damage. In the neurons of CAMKII-promoter driven p25 transgenic mice, p25 induction results in upregulation of cell cycle proteins and double-stranded DNA breaks followed by neuronal death. (11) This response occurs as a result of p25’s interaction with, and inactivation of, histone deacetylase 1 (HDAC1). HDAC1 is crucial to the transcriptional repression of cell cycle genes. (72) When inactivated, either through small interfering RNA (siRNA) knockdown or pharmacological inhibition, double stranded DNA breaks, increased cell cycle protein expression, and neuronal death occur. (72) The failure of p25 to suppress cell-cycle reentry via disruption of the E2F1-DP1 complex, as well as its role in initiating cell cycle re-entry by inactivating HDAC1, provides additional insight into the ways in which p25 contributes to neuronal death in neurodegenerative disease.

5. Cdk5 Involvement in Neurodegenerative Disease

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5.1. Alzheimer’s Disease

Alzheimer’s disease is a progressive neurodegenerative disorder associated with memory loss, cognitive function impairment, behavioral changes, and death. The pathophysiological hallmarks of AD include the formation of neurofibrillary tangles (NFTs) and β-amyloid (Aβ) plaques. The dysregulation of Cdk5 underlies the development of these aberrant structures and contributes to neuronal loss in AD through various additional mechanisms. The dysregulated Cdk5–p25 complex has a longer half-life than Cdk5–p35 and has a different subcellular localization. The resultant hyperactivation and mislocalization of Cdk5 leads to hyperphosphorylation of its physiological substrates and phosphorylation of nonphysiological targets. (14,73)
An important substrate subject to hyperphosphorylation by dysregulated Cdk5 is tau, a MAP that stabilizes MTs and drives neurite outgrowth. (74) As an abnormally large number of phosphate molecules are added onto tau by Cdk5–p25, tau detaches from the microtubules and self-aggregates to form paired helical fragments (PHFs) and insoluble NFTs within the neuron. (75) The inclusions, as well as the destabilized and disassembling MTs, impair axonal transport, diminish neural communication, and ultimately lead to neuronal death. (76−78) Knockdown of Cdk5 in triple-transgenic AD mice as well as Cdk5 inhibition by Cdk5 inhibitory peptide (CIP) in vitro has been shown to reduce tau hyperphosphorylation and NFT formation. (79−81) Cdk5 works in concert with an additional major tau kinase, GSK3β, to generate tau pathology. In young transgenic mice, Cdk5 has a negative regulatory effect on GSK3β. (82) However, in later stages of the disease, Cdk5 and GSK3β synergize to cause hyperphosphorylation, with Cdk5 priming phosphorylation sites on tau for GSK3β. (83,84) Dual inhibition of Cdk5–p25 and GSK3β is being investigated as a means to address tau pathology in AD and the combination has demonstrated neuroprotective properties in vitro and in vivo. (85)
The extracellular Aβ plaques found in AD are composed of oligomerized β-amyloid peptide. Aβ is derived from amyloid precursor protein (APP) after sequential cleavage by β-secretase 1 (BACE1) and γ-secretase (Figure 3). (86) Differing cleavage points on APP during γ-secretase processing result in two main forms of Aβ, Aβ40 and Aβ42. Aβ42 is regarded as the more neurotoxic peptide given its greater proclivity toward oligomerization. (87) Aβ42 instigates Cdk5 dysregulation by augmenting calpain activity and driving production of p25. (88) In a positive feedback looplike relationship, aberrant Cdk5–p25 activation results in elevated transcription of BACE1 by phosphorylating and activating signal transducer and activator of transcription 3 (STAT3) leading to increased cleavage of APP and accumulation of Aβ. (89−91) Additionally, hyperphosphorylation of APP at site Thr668 by Cdk5 significantly increases Aβ secretions. (92) Cdk5 indirectly increases APP trafficking and Aβ production by inducing Golgi fragmentation, a phenomenon observed in the neurons of AD patients. (93) The Golgi apparatus is involved in trafficking and processing APP and its cleaving enzymes. When Golgi tethering proteins such as GM130 are phosphorylated by Cdk5, associated Golgi structural proteins such as GRASP65 are in turn affected, resulting in Golgi fragmentation. (18) Golgi fragmentation leads to accelerated vesicle budding from the Golgi membrane allowing for an increased rate of APP trafficking and Aβ production. (94) Inhibition of Cdk5, or the expression of a nonphosphorylatable mutant of GRASP65, rescues the Golgi structure and results in decreased Aβ production. (94)

Figure 3

Figure 3. Aβ, derived from APP after cleavage by BACE and γ-secretase, induces calcium influx, activating calpain-mediated cleavage of p35 to p25. Cdk5 is hyperactivated by p25 that leads to hyperphosphorylation of Cdk5 targets. Cdk5–p25 and GSK3β, another tau kinase, work in concert to hyperphosphorylate tau, causing it to detach from MTs and aggregate to form PHFs and NFTs within the neuron. The NFTs and destabilized MTs impair axonal transport, disrupt intracellular communication, and cause neuronal death. Cdk5–p25 directly and indirectly increases Aβ production. Cdk5–p25 directly phosphorylates APP leading to increased Aβ production. Cdk5–p25 phosphorylates STAT3, causing increased BACE activity and transcription leading to increased cleavage of APP. Additionally, Cdk5–p25 induces Golgi fragmentation by phosphorylating Golgi tethering protein GM130, which interacts with the Golgi structural protein, GRASP 65, causing aberrant processing of APP. Aβ instigates mitochondrial fragmentation by increasing mitochondrial fission and Cdk5–p25 reduces the activity of Px2 to cause excessive accumulation of ROS, leading to oxidative stress and neuronal death. Excessive ROS disrupts intracellular calcium levels, further dysregulating Cdk5 activity.

The toxicity of the deposited insoluble Aβ plaques is controversial given the past findings that plaque burden does not correlate with disease symptoms and that plaques are sometimes present in individuals with normal cognitive function. (95,96) More recently, it has been suggested that it is instead the soluble Aβ oligomers surrounding the plaques that are mediating neurodegeneration. (97) Soluble Aβ42 oligomers induce synaptic degeneration and apoptosis by targeting mitochondrial membranes, increasing reactive oxygen species (ROS) levels, exacerbating neuroinflammation, and severely disrupting intracellular calcium homeostasis. (98,99) Reducing levels of Aβ oligomers has been demonstrated to improve cognitive function in mice. (100) However, in humans, Aβ as well as the secretases involved in producing Aβ have proved to be challenging therapeutic targets. (101)
Induction of mitochondrial and nuclear fragmentation constitute two additional mechanisms by which Cdk5 dysregulation contributes to neuronal cell loss in AD. Cdk5–p25 phosphorylates the nuclear envelope associating proteins lamin A and lamin B to induce rapid nuclear laminar dispersion, leading to neuronal apoptosis. (17) Mitochondrial fragmentation, that occurs as a result of increased mitochondrial fission and decreased fusion, (102) disrupts mitochondrial function leading to depletion of ATP, excessive production of ROS, and release of apoptotic factors. (16) Aβ oligomers, elevated as a result of Cdk5 dysregulation, decrease the expression of the mitochondrial fusion protein mitofusin 2 (Mfn2), resulting in extensive mitochondrial fission. (103) Furthermore, reduced mitochondrial length is seen in response to Aβ oligomer exposure. (104) Cdk5–p25 further contributes to oxidative stress by phosphorylating Prx2 at T89, reducing its antioxidant activity. (16,105) Resultantly, ROS accumulate and intracellular calcium levels increase, conditions that further dysregulate Cdk5 and create a vicious cycle leading to neuronal loss in AD. (16)

5.2. Parkinson’s Disease

Parkinson’s disease is the most common neurodegenerative movement disorder and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Degraded neurons are pathologically distinguished by the presence of Lewy bodies, cytoplasmic protein aggregates primarily composed of α-synuclein. (106) Cdk5 dysregulation has become increasingly associated with dopaminergic loss and the development of PD. Early studies demonstrated that elevated Cdk5–p25 correlates with the loss of dopaminergic neurons in mice injected with MPTP, a toxin used to damage the nigrostriatal dopaminergic pathway and model PD. (19) Inhibition of Cdk5 in this model significantly reduced MPTP-induced cell death. In addition, dopaminergic neurons in PD models demonstrate an elevated ratio of p25 to p35, (107) suggesting the presence of Cdk5 dysregulation, and Lewy bodies have been shown to be immune reactive with Cdk5. (108)
Cdk5 instigates neuronal cell loss in PD via several pathological mechanisms that remain under active investigation. Accumulating evidence suggests that mitochondrial dysfunction and subsequent oxidative stress are key mechanisms underlying both the familial and idiopathic forms of PD. (109,110) Indeed, many of the pathological mutations associated with familial forms of the disease are directly linked to mitochondrial impairment. (111) Cdk5 contributes to mitochondrial dysfunction in PD by phosphorylating several key proteins involved in the regulation of mitochondrial fission and mitophagy. Cdk5 phosphorylates Drp1, a mitochondrial fission controlling protein, at S616. (112) In a nonhuman primate model of PD, levels of p25 and p35 increase in response to MPTP injection leading to hyperactivation of Cdk5, excessive Drp1-mediated mitochondrial fragmentation, and dopaminergic neuronal loss. (112) Parkin, a cytosolic E3 ubiquitin ligase, and PINK1, a mitochondrial protein kinase, are crucial to mitochondrial quality control. PINK1 recognizes damaged and dysfunctional mitochondria and subsequently recruits and activates parkin to initiate their ubiquitination and mitophagy. (113) Phosphorylation of parkin at residue S131 by Cdk5 reduces its ubiquitin ligase activity, reducing its ability to degrade toxic protein aggregates such as synphilin-1/α-synuclein inclusions and potentially abrogating its mitophagy initiation. (113,114)
Impaired mitochondrial function and accumulation of damaged mitochondria leads to a dramatic increase in ROS accumulation and, thus, massive oxidative stress. (115) The presence of significant DNA damage, protein oxidation, lipid peroxidation, and increased iron deposition in PD patient brains establishes oxidative stress as critical to the pathogenesis of PD. (106,115) In addition to promoting mitochondria fragmentation and impairing mitophagy, Cdk5 contributes to oxidative stress by disrupting antioxidative cellular defenses. Cdk5 phosphorylates antioxidant enzyme Prx2 at T89 in vivo and in vitro, reducing its peroxidase activity following MPTP treatment and leading to increased oxidative load and neuronal death. (105) Cdk5 phosphorylates several other downstream targets involved in the MPTP induced cell death pathway. Myocyte enhancing factor 2 (MEF2), a transcription factor promoting the survival of neurons, is a substrate of Cdk5 both in vitro and in vivo. (116) Phosphorylation of MEF2 by Cdk5 at Ser444, a critical regulatory site, inhibits the prosurvival function of MEF2 and mediates dopaminergic death in response to MPTP. (116) Additionally, Cdk5 phosphorylates DNA repair enzyme apurinic/apyrimidinic endonuclease 1 (Ape1) at Thr232 that reduces its endonuclease activity resulting in accumulation of ROS induced DNA damage and eventually apoptosis (Figure 4). (117)

Figure 4

Figure 4. Mechanisms contributing to the loss of dopaminergic neurons in PD include mitochondrial dysfunction, oxidative stress, as well as aberrant autophagy and impaired protein clearance pathways. Cdk5 contributes to the pathogenesis of PD by phosphorylating key proteins, such as Ape1, Drp1, Px2, Parkin, MEF2, and EndoB1 that are involved in the aforementioned processes.

Autophagy is a homeostatic mechanism responsible for degrading and recycling dysfunctional proteins and organelles. Aberrant autophagy has become increasingly recognized as playing a crucial role in the pathogenesis of PD. (118) Autophagy is critical to the clearance of α-synuclein inclusions as well as other toxic protein aggregates. (119,120) Furthermore, in atg5/atg7 deficient mice, autophagy suppression results in motor deficits and neuronal death. (121) Conversely, excessive autophagy can be deleterious, representing a form of self-cannibalism. (122) Cdk5 has been identified as a regulator of EndoB1, a protein implicated in autophagy induction. (123) Phosphorylation of EndoB1 at Thr145 by Cdk5 mediates the induction of autophagy in starved neurons, neurons treated with MPP+ (the toxic metabolite of MPTP), and neurons expressing mutant α-synuclein. (123) Autophagy induction contributes to neuronal loss following MPP+ treatment and knockdown of EndoB1 or Cdk5 expression abrogated MPP+ induced cell loss. This finding provides an additional mechanism by which Cdk5 may contribute to neuronal loss under neurotoxic conditions. Recently, inhibition of Cdk5 using CIP was shown to prevent the loss of dopaminergic neurons in MPTP induced PD mice. (124) Specific inhibition of Cdk5–p25 using a blood-brain barrier penetrable version of P5, a 24 amino acid peptide derived from CIP, also provided neuroprotection in MPTP models. (125) Therapeutic targeting to ameliorate the effects of Cdk5 dysregulation in PD remains an interesting avenue that requires further investigation.

5.3. Huntington’s Disease

Huntington’s disease is an autosomal dominant neurodegenerative disease predominantly caused by the production of mutant antiapoptotic huntingtin (mHTT) protein containing abnormally long polyglutamine (polyQ) repeats. Excessive cleavage of mHTT by calpains, caspases, and aspartic proteases leads to the accumulation of toxic fragments that cause degeneration in striatal neurons, and eventually, in the motor cortex. (126,127) Current evidence suggests that Cdk5–p35 activity is neuroprotective in Huntington’s. Cdk5–p35 has been shown to mitigate mHTT aggregation via phosphorylation of mHTT at Ser434, significantly reducing polyQ cleavage, accumulation, and subsequent toxicity. (20) This caspase blocking activity is further supported by a more recent study in which inhibition of Cdk5 correlated with increased fragment aggregation and cell death in spinocerebellar ataxia type3 positive cells, another neurodegenerative polyQ protein disease. (128) Additionally, Cdk5 was shown to phosphorylate mHTT at Ser1181 and Ser1201 in response to DNA damage in vivo and in vitro, preventing polyQ-induced p53 mediated toxicity and cell death in striatal neurons. (129) Lastly, intact microtubule cytoskeletons are required for mHTT aggregation. As previously mentioned, Cdk5 regulates the stability of the microtubule network through phosphorylation of MAPs. Cdk5–p35 was shown to suppress the inclusion of mHTT in primary neurons in accordance with destabilization of the microtubule network. (130,131)
Low Cdk5 and p35 levels are reported in the striatum of post-mortem HD patients and in HdhQ111 mutant mice. (20,132) Increased mHTT levels correspond with inhibition of Cdk5 activity, decreased Cdk5 expression, and increased conversion of p35 to p25, implicating mHTT as a potential modulator of the Cdk5 pathway. (132) Increased Cdk5–p25 activity, in addition to decreased Cdk5–p35 activity, may contribute to HD pathology. (133) Therapeutics that mimic or stimulate Cdk5–p35 activity, or prevent Cdk5–p25 activity, may be beneficial for treatment of the disease.

6. Drug Discovery Approaches for Inhibiting Cdk5 Activity

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Given Cdk5’s capacity to drive the pathological events leading to the development of neurodegenerative disease, Cdk5 is an attractive drug target for these indications. However, considering the multifaceted physiological role Cdk5–p35 plays in the adult brain, specific inhibition of the Cdk5–p25 complex is necessary to abrogate Cdk5’s pathological features while retaining its normal function. Although the following three classes of Cdk5 inhibitors have been described in the literature as inhibiting Cdk5–p25 activity, no specific Cdk5 inhibitor has, to our knowledge, ever entered clinical trials.

6.1. Targeting ATP-Binding and Non-ATP Binding Regions on Cdk5

Several high-potency pharmacological small molecule inhibitors of Cdk5 have been described under this approach. (22,134−139) The cocrystal structures and molecular docking studies of those inhibitors bound to Cdk5 reveals that they directly compete with ATP for binding the ATP pocket within the kinase domain (Figure 5A). (13,138) Achieving high selectivity for Cdk5 over other Cdks is challenging using this approach due to amino acid sequence similarities in the ATP binding pocket. For example, Roscovitine inhibits Cdk1, Cdk2, Cdk5, Cdk7, and Cdk9, and to a lesser degree, Cdk4/6. Other first-generation ATP-competitive inhibitors, such as olomoucine and flavopiridol similarly demonstrate poor selectivity. Nonselective Cdk inhibitors are generally unfavorable and ineffective due to off-target toxic effects and severe side effect profiles, which limit dose-escalation. A broad range of chemical scaffolds (Table 1) have been discovered that directly compete with the ATP binding pocket of Cdk5, most of which have only been tested in cancer models. (22,138) Very few recently developed Cdk5 inhibitors have been tested in neurodegenerative disease models. (140−142)

Figure 5

Figure 5. Therapeutic strategies toward inhibiting pathological Cdk5 activity. (A) Nonselective: Small molecules that compete for the active ATP binding site within the kinase domain. (B) Selective: Disruption of protein–Cdk interaction using peptides. (C) Selective: Disruption of protein–Cdk interaction using small molecule inhibitors.

Table 1. Representative Cdk5 Inhibitors Using Different Targeting Strategies: Small Molecule Inhibitors (Targeting Either the ATP Binding Pocket or Other Non-ATP Site on Cdk5 Protein), Using Peptides to Disrupt the Protein–Protein Interaction between Cdk5–p25, or Using Small Molecules to Disrupt the Protein–Protein Interaction Between Cdk5–p25
small molecule inhibitors (ATP or non-ATP binding pockets
chemical scaffoldchemical nameCdk5/Cdk2 inhibition (IC50, μM)
purineroscovitineCdk5 = 0.27; Cdk2 = 0.22
 CR-8Cdk5 = 0.062; Cdk2 = 0.220
 BP 14Cdk5 = 0.015; Cdk2 = 0.050
 3JCdk5 = 0.017; Cdk2 = 0.038
 6bCdk5 = 0.18; Cdk2 = 0.007
thiazolePJBCdk5 = 0.098; Cdk2 = 0.064
pyrazo pyrimidineLGR 2674Cdk5 = 0.005; Cdk2 = 0.021
pyrimidineR547Cdk5 = 0.001; Cdk2 = 0.002
pyrazo pyridinedinaciclibCdk5 = 0.001; Cdk2 = 0.001
disruption of Cdk5–p25 PPI using peptides
12 amino acid CIP
24 amino acid P5
disruption of Cdk5–p25 PPI using small molecules
chemical scaffoldchemical nameCdk5 inhibition (IC50, μM)
triphenylethylenetamoxifenCdk5 = 0.010
Other non-ATP Cdk5 binding sites, such as the hinge region, glycine rich loop, gatekeeper residue Phe80, and surface specificity residue (e.g., Lys89) have been considered for designing more selective Cdk5 inhibitors. (143,144) These strategies have not demonstrated encouraging results for improved selectivity for Cdk5 over other Cdks, and in silico detection of binding sites in these regions is more difficult than in the ATP binding pockets. Targeting the inactive conformation of Cdk5 (DFG-out conformation) may allow for more selective inhibition compared to targeting Cdk5 in its active state. (145) However, no such DFG-out conformation of Cdk5 has been identified, requiring further development of in-depth in silico binding models in order to design these type-II inhibitors. Additionally, these aforementioned strategies inhibit the entire Cdk5 protein, preventing formation of the physiologically necessary Cdk5–p35 complex in addition to inhibiting Cdk5–p25 formation.

6.2. Disruption of Cdk5–Protein Interaction Using Peptides

An alternative strategy for selectively targeting Cdk5 utilizes peptides derived from its activators to disrupt the Cdk5–p25 binding interface (Figure 5B). Cdk5 inhibitory peptide (CIP), a 125 amino acid peptide derived from p35, binds to Cdk5 with higher affinity than both p25 and p35; however, it is unable to activate Cdk5 in vitro and, therefore, competitively inhibits Cdk5. (146) CIP was found to effectively and specifically inhibit Cdk5–p25 activity in cortical neurons without affecting endogenous Cdk5–p35 activity or the activity of other Cdks. (81,146) P5, a smaller 24 residue peptide derived from p25, shows more potent inhibition of Cdk5–p25 than CIP while retaining specificity. (147) The exact reason behind this specificity is yet to be fully elucidated, however, it is suggested that the N-terminal domain of p35, which is lacking in p25, may obstruct access of CIP or p5 to the Cdk5 active site. (81) Further studies on a modified blood-brain barrier penetrable version of p5, termed TFP5/TP5, demonstrated the peptide’s capacity to abrogate dopaminergic neuron death in a MPTP/MPP+ treated PD mouse model. (125) Unfortunately, due to the poor pharmacokinetics of peptides (low stability and short half-lives in vivo), (147,148) no CIP or p5 treatments have progressed to clinical trials. Clinical applications of p5 in treating neurodegenerative disease will require circumventing these limitations through methods such as peptide mimetics or peptide-based nanodelivery systems.

6.3. Disruption of Cdk5–Protein Interaction Using Small Molecules

More recently, small molecule protein–protein interaction (PPI) inhibitors have been investigated to disrupt the interactions between Cdk5 and p25 (Figure 5C). BRET-based PPI screening identified tamoxifen, an established treatment for estrogen-receptor-positive breast cancer, as an inhibitor of Cdk5 activity. Further chemical and in silico analysis revealed that tamoxifen binds specifically to p25, not Cdk5, preventing formation of the Cdk5–p25 dimer and significantly reducing tau pathology. (149,150) Protein–protein interaction based screening assays present a promising tool to identify additional PPI inhibitors of the Cdk5–p25 interaction. This strategy of identifying site-specific PPI inhibitors will allow for new selective therapies that retain Cdk5–p35’s physiological function.

7. Concluding Remarks and Future Directions

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Neurodegenerative diseases are debilitating and incurable conditions that continue to affect a growing number of individuals globally. There is an urgent need for therapies that can prevent, slow, or halt disease progression. The hallmarks of ND, as depicted by this review, include the formation of toxic protein aggregates, aberrant mitochondrial dynamics, oxidative stress, and neuroinflammation. Countless studies have evidenced that aberrant Cdk5 hyperactivity associated with its p25 activator represents a crucial mechanism underlying the development of these pathologies. Cdk5–p25’s multimodal involvement in conditions such as AD and PD make it an attractive therapeutic target for ND. As demonstrated in this review, the pivotal physiological role of Cdk5 must be considered when determining Cdk5 targeting strategies. A successful Cdk5 inhibitor for ND must pass the blood-brain barrier, specifically target Cdk5 while leaving other Cdks unaffected, and must abrogate the interaction of Cdk5 with p25 but not p35. ATP-competitive inhibitors, which remain popular as pan-Cdk inhibitors for cancer, are nonspecific and are unlikely to have a lasting effect on the course of Cdk5–p25 mediated pathology. Using peptides and small molecule PPI inhibitors, strategies which seek to disrupt the interfacing of p25 and Cdk5 are selective strategies. However, peptides are unlikely to be successful in vivo unless methods are devised to achieve targeted, effective delivery to the brain. Small molecule PPI inhibitors represent a promising strategy moving forward to satisfy the requisites of a successful Cdk5 inhibitor. Future therapies developed with a focus on selective strategies will provide significant benefit for patients suffering from ND.

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Author Information

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  • Corresponding Author
    • Venkata Mahidhar Yenugonda - Drug Discovery and Nanomedicine Laboratory, , John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health Center, Santa Monica, California 90404, United StatesOrcidhttp://orcid.org/0000-0001-5436-7957 Email: [email protected]
  • Authors
    • Annamarie B. Allnutt - Translational Neurosciences and Neurotherapeutics, , John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health Center, Santa Monica, California 90404, United States
    • Ariana K. Waters - Drug Discovery and Nanomedicine Laboratory, , John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health Center, Santa Monica, California 90404, United States
    • Santosh Kesari - Translational Neurosciences and Neurotherapeutics, , John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John’s Health Center, Santa Monica, California 90404, United States
  • Funding

    This supplement was supported by seed funding from JWCI, Saint John Foundation, Pacific Neuroscience Institute Foundation, FFANY and ABC’s foundation to Drug Discovery and Nanomedicine laboratory

  • Notes
    The authors declare no competing financial interest.

Abbreviations

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amyloid beta

AD

Alzheimer’s disease

APP

amyloid precursor protein

BACE1

β-secretase 1

Cdk5

cyclin dependent kinase 5

CIP

Cdk5 inhibitory peptide

CP

cortical plate

Drp1

dynamin related protein 1

EGL

external granule layer

EndoB1

endophilin B1

GCPs

granule cell precursors

GSK3β

glycogen synthase kinase 3 beta

HDAC1

histone deacetylase 1

HD

Huntington’s disease

IGL

internal granule layer

LTP

long-term potentiation

MAPs

microtubule associated protein

MAP1B

microtubule associated protein 1B

Mfn2

mitochondrial fusion protein 2

MHB-Cdk5 KO

midbrain-hindbrain specific Cdk5 conditional knockout

mHTT

mutant anti apoptotic huntingtin

MPP+

1-methyl-4-phenylpyridinium

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MTs

microtubules

MZ

marginal zone

Ncad

N-cadherin

NFT

neurofibrillary tangles

NGF

nerve-growth factor

NMDAR

NMDA receptor

PCs

Purkinje cells

PCL

Purkinje cell layer

PD

Parkinson’s disease

PHFs

paired helical fragments

PINK1

PTEN-induced kinase 1

PolyQ

polyglutamine

Prx 1/2

peroxiredoxin 1 and 2

ROS

reactive oxygen species

Shh

Sonic hedgehog

siPs

small interfering peptides

siRNA

small interfering RNA

STAT3

signal transducer and activator of transcription 3

SVZ

subventricular zone

SVZ-IZ

subventricular-intermediate zone

VZ

ventricular zone

References

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This article references 150 other publications.

  1. 1
    Malumbres, M., Harlow, E., Hunt, T., Hunter, T., Lahti, J. M., Manning, G., Morgan, D. O., Tsai, L. H., and Wolgemuth, D. J. (2009) Cyclin-dependent kinases: a family portrait. Nat. Cell Biol. 11, 12751276,  DOI: 10.1038/ncb1109-1275
  2. 2
    Malumbres, M. (2014) Cyclin-dependent kinases. Genome Biol. 15, 122,  DOI: 10.1186/gb4184
  3. 3
    Lee, M. G. and Nurse, P. (1987) Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2. Nature 327, 3135,  DOI: 10.1038/327031a0
  4. 4
    Andzelm, E. R., Lew, J., and Taylor, S. (1995) Bound to activate: conformational consequences of cyclin binding to CDK2. Structure 3, 11351141,  DOI: 10.1016/S0969-2126(01)00249-0
  5. 5
    Xiong, Y., Zhang, H., and Beach, D. (1992) D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 71, 505514,  DOI: 10.1016/0092-8674(92)90518-H
  6. 6
    Ishiguro, K., Takamatsu, M., Tomizawa, K., Omori, A., Takahashi, M., Arioka, M., Uchida, T., and Imahori, K. (1992) Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. J. Biol. Chem. 267, 1089710901
  7. 7
    Hellmich, M. R., Pant, H. C., Wada, E., and Battey, J. F. (1992) Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc. Natl. Acad. Sci. U. S. A. 89, 1086710871,  DOI: 10.1073/pnas.89.22.10867
  8. 8
    Cruz, J. C., Tseng, H. C., Goldman, J. A., Shih, H., and Tsai, L. H. (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40, 471483,  DOI: 10.1016/S0896-6273(03)00627-5
  9. 9
    Lopes, J. P. and Agostinho, P. (2011) Cdk5: multitasking between physiological and pathological conditions. Prog. Neurobiol. 94, 4963,  DOI: 10.1016/j.pneurobio.2011.03.006
  10. 10
    Zhang, J., Li, H., Yabut, O., Fitzpatrick, H., D’Arcangelo, G., and Herrup, K. (2010) Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex. J. Neurosci. 30, 52195228,  DOI: 10.1523/JNEUROSCI.5628-09.2010
  11. 11
    Kim, D., Frank, C. L., Dobbin, M. M., Tsunemoto, R. K., Tu, W., Peng, P. L., Guan, J. S., Lee, B. H., Moy, L. Y., Giusti, P., Broodie, N., Mazitschek, R., Delalle, I., Haggarty, S. J., Neve, R. L., Lu, Y., and Tsai, L. H. (2008) Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 60, 803817,  DOI: 10.1016/j.neuron.2008.10.015
  12. 12
    Chang, K. H., Vincent, F., and Shah, K. (2012) Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death. J. Cell Sci. 125, 51245137,  DOI: 10.1242/jcs.108183
  13. 13
    Tarricone, C., Dhavan, R., Peng, J., Areces, L. B., Tsai, L. H., and Musacchio, A. (2001) Structure and regulation of the CDK5-p25(nck5a) complex. Mol. Cell 8, 657669,  DOI: 10.1016/S1097-2765(01)00343-4
  14. 14
    Patrick, G. N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., and Tsai, L. H. (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615622,  DOI: 10.1038/45159
  15. 15
    Wilkaniec, A., Czapski, G. A., and Adamczyk, A. (2016) Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses. J. Neurochem. 136, 222233,  DOI: 10.1111/jnc.13365
  16. 16
    Sun, K. H., de Pablo, Y., Vincent, F., and Shah, K. (2008) Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction. J. Neurochem. 107, 265278,  DOI: 10.1111/j.1471-4159.2008.05616.x
  17. 17
    Chang, K. H., Multani, P. S., Sun, K. H., Vincent, F., de Pablo, Y., Ghosh, S., Gupta, R., Lee, H. P., Lee, H. G., Smith, M. A., and Shah, K. (2011) Nuclear envelope dispersion triggered by deregulated Cdk5 precedes neuronal death. Mol. Biol. Cell 22, 14521462,  DOI: 10.1091/mbc.e10-07-0654
  18. 18
    Sun, K. H., de Pablo, Y., Vincent, F., Johnson, E. O., Chavers, A. K., and Shah, K. (2008) Novel genetic tools reveal Cdk5′s major role in Golgi fragmentation in Alzheimer’s disease. Mol. Biol. Cell 19, 30523069,  DOI: 10.1091/mbc.e07-11-1106
  19. 19
    Smith, P. D., Crocker, S. J., Jackson-Lewis, V., Jordan-Sciutto, K. L., Hayley, S., Mount, M. P., O’Hare, M. J., Callaghan, S., Slack, R. S., Przedborski, S., Anisman, H., and Park, D. S. (2003) Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease. Proc. Natl. Acad. Sci. U. S. A. 100, 1365013655,  DOI: 10.1073/pnas.2232515100
  20. 20
    Luo, S., Vacher, C., Davies, J. E., and Rubinsztein, D. C. (2005) Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J. Cell Biol. 169, 647656,  DOI: 10.1083/jcb.200412071
  21. 21
    Liebl, J., Fürst, R., Vollmar, A. M., and Zahler, S. (2011) Twice switched at birth: cell cycle-independent roles of the ″neuron-specific″ cyclin-dependent kinase 5 (Cdk5) in non-neuronal cells. Cell. Signalling 23, 16981707,  DOI: 10.1016/j.cellsig.2011.06.020
  22. 22
    Pozo, K. and Bibb, J. A. (2016) The Emerging Role of Cdk5 in Cancer. Trends Cancer 2, 606618,  DOI: 10.1016/j.trecan.2016.09.001
  23. 23
    Shetty, K. T., Link, W. T., and Pant, H. C. (1993) cdc2-like kinase from rat spinal cord specifically phosphorylates KSPXK motifs in neurofilament proteins: isolation and characterization. Proc. Natl. Acad. Sci. U. S. A. 90, 68446848,  DOI: 10.1073/pnas.90.14.6844
  24. 24
    Beaudette, K. N., Lew, J., and Wang, J. H. (1993) Substrate specificity characterization of a cdc2-like protein kinase purified from bovine brain. J. Biol. Chem. 268, 2082520830
  25. 25
    Meyerson, M., Enders, G. H., Wu, C. L., Su, L. K., Gorka, C., Nelson, C., Harlow, E., and Tsai, L. H. (1992) A family of human cdc2-related protein kinases. EMBO J. 11, 29092917,  DOI: 10.1002/j.1460-2075.1992.tb05360.x
  26. 26
    Tsai, L.-H., Delalle, I., Caviness, V. S., Chae, T., and Harlow, E. (1994) p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371, 419423,  DOI: 10.1038/371419a0
  27. 27
    Tang, D., Yeung, J., Lee, K.-Y., Matsushita, M., Matsui, H., Tomizawa, K., Hatase, O., and Wang, J. H. (1995) An Isoform of the Neuronal Cyclin-dependent Kinase 5 (Cdk5) Activator. J. Biol. Chem. 270, 2689726903,  DOI: 10.1074/jbc.270.45.26897
  28. 28
    Cruz, J. C. and Tsai, L. H. (2004) A Jekyll and Hyde kinase: roles for Cdk5 in brain development and disease. Curr. Opin. Neurobiol. 14, 390394,  DOI: 10.1016/j.conb.2004.05.002
  29. 29
    Tang, D. and Wang, J. H. (1996) Cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activators. Prog. Cell Cycle Res. 2, 205216,  DOI: 10.1007/978-1-4615-5873-6_20
  30. 30
    Hisanaga, S.-i. and Saito, T. (2003) The regulation of cyclin-dependent kinase 5 activity through the metabolism of p35 or p39 Cdk5 activator. Neurosignals 12, 221229,  DOI: 10.1159/000074624
  31. 31
    Lee, K. Y., Rosales, J. L., Tang, D., and Wang, J. H. (1996) Interaction of cyclin-dependent kinase 5 (Cdk5) and neuronal Cdk5 activator in bovine brain. J. Biol. Chem. 271, 15381543,  DOI: 10.1074/jbc.271.3.1538
  32. 32
    Zhu, Y.-S., Saito, T., Asada, A., Maekawa, S., and Hisanaga, S.-i. (2005) Activation of latent cyclin-dependent kinase 5 (Cdk5)–p35 complexes by membrane dissociation. J. Neurochem. 94, 15351545,  DOI: 10.1111/j.1471-4159.2005.03301.x
  33. 33
    Wei, F. Y., Tomizawa, K., Ohshima, T., Asada, A., Saito, T., Nguyen, C., Bibb, J. A., Ishiguro, K., Kulkarni, A. B., Pant, H. C., Mikoshiba, K., Matsui, H., and Hisanaga, S. (2005) Control of cyclin-dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability. J. Neurochem. 93, 502512,  DOI: 10.1111/j.1471-4159.2005.03058.x
  34. 34
    Liu, S. L., Wang, C., Jiang, T., Tan, L., Xing, A., and Yu, J. T. (2016) The Role of Cdk5 in Alzheimer’s Disease. Mol. Neurobiol. 53, 43284342,  DOI: 10.1007/s12035-015-9369-x
  35. 35
    Matsuura, I. and Wang, J. H. (1996) Demonstration of Cyclin-dependent Kinase Inhibitory Serine/Threonine Kinase in Bovine Thymus. J. Biol. Chem. 271, 54435450,  DOI: 10.1074/jbc.271.10.5443
  36. 36
    Sharma, P., Sharma, M., Amin, N. D., Albers, R. W., and Pant, H. C. (1999) Regulation of cyclin-dependent kinase 5 catalytic activity by phosphorylation. Proc. Natl. Acad. Sci. U. S. A. 96, 1115611160,  DOI: 10.1073/pnas.96.20.11156
  37. 37
    Asada, A., Yamamoto, N., Gohda, M., Saito, T., Hayashi, N., and Hisanaga, S. (2008) Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cyclin-dependent kinase 5 complexes. J. Neurochem. 106, 13251336,  DOI: 10.1111/j.1471-4159.2008.05500.x
  38. 38
    Ohshima, T., Ward, J. M., Huh, C. G., Longenecker, G., Veeranna, Pant, H. C., Brady, R. O., Martin, L. J., and Kulkarni, A. B. (1996) Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl. Acad. Sci. U. S. A. 93, 1117311178,  DOI: 10.1073/pnas.93.20.11173
  39. 39
    Ohshima, T., Gilmore, E. C., Longenecker, G., Jacobowitz, D. M., Brady, R. O., Herrup, K., and Kulkarni, A. B. (1999) Migration defects of cdk5(−/−) neurons in the developing cerebellum is cell autonomous. J. Neurosci. 19, 60176026,  DOI: 10.1523/JNEUROSCI.19-14-06017.1999
  40. 40
    Gilmore, E. C., Ohshima, T., Goffinet, A. M., Kulkarni, A. B., and Herrup, K. (1998) Cyclin-dependent kinase 5-deficient mice demonstrate novel developmental arrest in cerebral cortex. J. Neurosci. 18, 63706377,  DOI: 10.1523/JNEUROSCI.18-16-06370.1998
  41. 41
    Ko, J., Humbert, S., Bronson, R. T., Takahashi, S., Kulkarni, A. B., Li, E., and Tsai, L.-H. (2001) p35 and p39 Are Essential for Cyclin-Dependent Kinase 5 Function during Neurodevelopment. J. Neurosci. 21, 67586771,  DOI: 10.1523/JNEUROSCI.21-17-06758.2001
  42. 42
    Nadarajah, B., Brunstrom, J. E., Grutzendler, J., Wong, R. O., and Pearlman, A. L. (2001) Two modes of radial migration in early development of the cerebral cortex. Nat. Neurosci. 4, 143150,  DOI: 10.1038/83967
  43. 43
    Tabata, H. and Nakajima, K. (2003) Multipolar Migration: The Third Mode of Radial Neuronal Migration in the Developing Cerebral Cortex. J. Neurosci. 23, 999610001,  DOI: 10.1523/JNEUROSCI.23-31-09996.2003
  44. 44
    Noctor, S. C., Martinez-Cerdeno, V., Ivic, L., and Kriegstein, A. R. (2004) Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat. Neurosci. 7, 136144,  DOI: 10.1038/nn1172
  45. 45
    Kawauchi, T., Chihama, K., Nabeshima, Y., and Hoshino, M. (2006) Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration. Nat. Cell Biol. 8, 1726,  DOI: 10.1038/ncb1338
  46. 46
    Ohshima, T., Hirasawa, M., Tabata, H., Mutoh, T., Adachi, T., Suzuki, H., Saruta, K., Iwasato, T., Itohara, S., Hashimoto, M., Nakajima, K., Ogawa, M., Kulkarni, A. B., and Mikoshiba, K. (2007) Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex. Development 134, 22732282,  DOI: 10.1242/dev.02854
  47. 47
    Nishimura, Y. V., Sekine, K., Chihama, K., Nakajima, K., Hoshino, M., Nabeshima, Y., and Kawauchi, T. (2010) Dissecting the factors involved in the locomotion mode of neuronal migration in the developing cerebral cortex. J. Biol. Chem. 285, 58785887,  DOI: 10.1074/jbc.M109.033761
  48. 48
    Homayouni, R. and Curran, T. (2000) Cortical development: Cdk5 gets into sticky situations. Curr. Biol. 10, R331334,  DOI: 10.1016/S0960-9822(00)00459-0
  49. 49
    Kwon, Y. T., Gupta, A., Zhou, Y., Nikolic, M., and Tsai, L. H. (2000) Regulation of N-cadherin-mediated adhesion by the p35-Cdk5 kinase. Curr. Biol. 10, 363372,  DOI: 10.1016/S0960-9822(00)00411-5
  50. 50
    Lee, D.-K., Lee, H., Yoon, J., Hong, S., Lee, Y., Kim, K.-T., Kim, J. W., and Song, M.-R. (2019) Cdk5 regulates N-cadherin-dependent neuronal migration during cortical development. Biochem. Biophys. Res. Commun. 514, 645652,  DOI: 10.1016/j.bbrc.2019.04.166
  51. 51
    Marin, O., Valiente, M., Ge, X., and Tsai, L. H. (2010) Guiding neuronal cell migrations. Cold Spring Harbor Perspect. Biol. 2, a001834,  DOI: 10.1101/cshperspect.a001834
  52. 52
    Chae, T., Kwon, Y. T., Bronson, R., Dikkes, P., Li, E., and Tsai, L. H. (1997) Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18, 2942,  DOI: 10.1016/S0896-6273(01)80044-1
  53. 53
    Joseph Altman, S. A. B. (1997) Development of the cerebellar system: in relation to its evolution, structure, and functions, CRC Press, Boca Raton, FL.
  54. 54
    Corrales, J. D., Blaess, S., Mahoney, E. M., and Joyner, A. L. (2006) The level of sonic hedgehog signaling regulates the complexity of cerebellar foliation. Development 133, 18111821,  DOI: 10.1242/dev.02351
  55. 55
    Komuro, H., Yacubova, E., Yacubova, E., and Rakic, P. (2001) Mode and Tempo of Tangential Cell Migration in the Cerebellar External Granular Layer. J. Neurosci. 21, 527,  DOI: 10.1523/JNEUROSCI.21-02-00527.2001
  56. 56
    Hatanaka, Y., Yamauchi, K., and Murakami, F. (2012) Formation of axon-dendrite polarity in situ: initiation of axons from polarized and non-polarized cells. Dev Growth Differ 54, 398407,  DOI: 10.1111/j.1440-169X.2012.01344.x
  57. 57
    Kumazawa, A., Mita, N., Hirasawa, M., Adachi, T., Suzuki, H., Shafeghat, N., Kulkarni, A. B., Mikoshiba, K., Inoue, T., and Ohshima, T. (2013) Cyclin-dependent kinase 5 is required for normal cerebellar development. Mol. Cell. Neurosci. 52, 97105,  DOI: 10.1016/j.mcn.2012.10.007
  58. 58
    Kapitein, L. C. and Hoogenraad, C. C. (2015) Building the Neuronal Microtubule Cytoskeleton. Neuron 87, 492506,  DOI: 10.1016/j.neuron.2015.05.046
  59. 59
    Shah, K. and Lahiri, D. K. (2017) A Tale of the Good and Bad: Remodeling of the Microtubule Network in the Brain by Cdk5. Mol. Neurobiol. 54, 22552268,  DOI: 10.1007/s12035-016-9792-7
  60. 60
    Brown, M., Jacobs, T., Eickholt, B., Ferrari, G., Teo, M., Monfries, C., Qi, R. Z., Leung, T., Lim, L., and Hall, C. (2004) Alpha2-chimaerin, cyclin-dependent Kinase 5/p35, and its target collapsin response mediator protein-2 are essential components in semaphorin 3A-induced growth-cone collapse. J. Neurosci. 24, 89949004,  DOI: 10.1523/JNEUROSCI.3184-04.2004
  61. 61
    Plattner, F., Hernandez, A., Kistler, T. M., Pozo, K., Zhong, P., Yuen, E. Y., Tan, C., Hawasli, A. H., Cooke, S. F., Nishi, A., Guo, A., Wiederhold, T., Yan, Z., and Bibb, J. A. (2014) Memory enhancement by targeting Cdk5 regulation of NR2B. Neuron 81, 10701083,  DOI: 10.1016/j.neuron.2014.01.022
  62. 62
    Li, B. S., Sun, M. K., Zhang, L., Takahashi, S., Ma, W., Vinade, L., Kulkarni, A. B., Brady, R. O., and Pant, H. C. (2001) Regulation of NMDA receptors by cyclin-dependent kinase-5. Proc. Natl. Acad. Sci. U. S. A. 98, 1274212747,  DOI: 10.1073/pnas.211428098
  63. 63
    Fischer, A., Sananbenesi, F., Pang, P. T., Lu, B., and Tsai, L.-H. (2005) Opposing Roles of Transient and Prolonged Expression of p25 in Synaptic Plasticity and Hippocampus-Dependent Memory. Neuron 48, 825838,  DOI: 10.1016/j.neuron.2005.10.033
  64. 64
    Plattner, F., Giese, K. P., and Angelo, M. (2008) Involvement of Cdk5 in synaptic plasticity, and learning and memory. In Cyclin Dependent Kinase 5 (Cdk5) (Ip, N. Y., and Tsai, L.-H., Eds.), Springer US, Boston, MA.
  65. 65
    Zhang, S., Edelmann, L., Liu, J., Crandall, J. E., and Morabito, M. A. (2008) Cdk5 Regulates the Phosphorylation of Tyrosine 1472 NR2B and the Surface Expression of NMDA Receptors. J. Neurosci. 28, 415,  DOI: 10.1523/JNEUROSCI.1900-07.2008
  66. 66
    Crair, M. C. and Malenka, R. C. (1995) A critical period for long-term potentiation at thalamocortical synapses. Nature 375, 325328,  DOI: 10.1038/375325a0
  67. 67
    Tang, Y. P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, M., Liu, G., and Tsien, J. Z. (1999) Genetic enhancement of learning and memory in mice. Nature 401, 6369,  DOI: 10.1038/43432
  68. 68
    Frade, J. M. and Ovejero-Benito, M. C. (2015) Neuronal cell cycle: the neuron itself and its circumstances. Cell Cycle 14, 712720,  DOI: 10.1080/15384101.2015.1004937
  69. 69
    Folch, J., Junyent, F., Verdaguer, E., Auladell, C., Pizarro, J. G., Beas-Zarate, C., Pallas, M., and Camins, A. (2012) Role of cell cycle re-entry in neurons: a common apoptotic mechanism of neuronal cell death. Neurotoxic. Res. 22, 195207,  DOI: 10.1007/s12640-011-9277-4
  70. 70
    Seward, M. E., Swanson, E., Norambuena, A., Reimann, A., Cochran, J. N., Li, R., Roberson, E. D., and Bloom, G. S. (2013) Amyloid-beta signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer’s disease. J. Cell Sci. 126, 12781286,  DOI: 10.1242/jcs.1125880
  71. 71
    Herrup, K. and Busser, J. C. (1995) The induction of multiple cell cycle events precedes target-related neuronal death. Development 121, 23852395
  72. 72
    Lagger, G., O’Carroll, D., Rembold, M., Khier, H., Tischler, J., Weitzer, G., Schuettengruber, B., Hauser, C., Brunmeir, R., Jenuwein, T., and Seiser, C. (2002) Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. Embo j 21, 26722681,  DOI: 10.1093/emboj/21.11.2672
  73. 73
    Qu, J., Nakamura, T., Cao, G., Holland, E. A., McKercher, S. R., and Lipton, S. A. (2011) S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by beta-amyloid peptide. Proc. Natl. Acad. Sci. U. S. A. 108, 1433014335,  DOI: 10.1073/pnas.1105172108
  74. 74
    Drubin, D. G. and Kirschner, M. W. (1986) Tau protein function in living cells. J. Cell Biol. 103, 27392746,  DOI: 10.1083/jcb.103.6.2739
  75. 75
    Iqbal, K., Liu, F., and Gong, C. X. (2016) Tau and neurodegenerative disease: the story so far. Nat. Rev. Neurol. 12, 1527,  DOI: 10.1038/nrneurol.2015.225
  76. 76
    Hong, M., Zhukareva, V., Vogelsberg-Ragaglia, V., Wszolek, Z., Reed, L., Miller, B. I., Geschwind, D. H., Bird, T. D., McKeel, D., Goate, A., Morris, J. C., Wilhelmsen, K. C., Schellenberg, G. D., Trojanowski, J. Q., and Lee, V. M. (1998) Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 19141917,  DOI: 10.1126/science.282.5395.1914
  77. 77
    Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., Pickering-Brown, S., Chakraverty, S., Isaacs, A., Grover, A., Hackett, J., Adamson, J., Lincoln, S., Dickson, D., Davies, P., Petersen, R. C., Stevens, M., de Graaff, E., Wauters, E., van Baren, J., Hillebrand, M., Joosse, M., Kwon, J. M., Nowotny, P., Che, L. K., Norton, J., Morris, J. C., Reed, L. A., Trojanowski, J., Basun, H., Lannfelt, L., Neystat, M., Fahn, S., Dark, F., Tannenberg, T., Dodd, P. R., Hayward, N., Kwok, J. B., Schofield, P. R., Andreadis, A., Snowden, J., Craufurd, D., Neary, D., Owen, F., Oostra, B. A., Hardy, J., Goate, A., van Swieten, J., Mann, D., Lynch, T., and Heutink, P. (1998) Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702705,  DOI: 10.1038/31508
  78. 78
    Buee, L., Troquier, L., Burnouf, S., Belarbi, K., Van der Jeugd, A., Ahmed, T., Fernandez-Gomez, F., Caillierez, R., Grosjean, M. E., Begard, S., Barbot, B., Demeyer, D., Obriot, H., Brion, I., Buee-Scherrer, V., Maurage, C. A., Balschun, D., D’Hooge, R., Hamdane, M., Blum, D., and Sergeant, N. (2010) From tau phosphorylation to tau aggregation: what about neuronal death?. Biochem. Soc. Trans. 38, 967972,  DOI: 10.1042/BST0380967
  79. 79
    Noble, W., Olm, V., Takata, K., Casey, E., Mary, O., Meyerson, J., Gaynor, K., LaFrancois, J., Wang, L., Kondo, T., Davies, P., Burns, M., Veeranna, Nixon, R., Dickson, D., Matsuoka, Y., Ahlijanian, M., Lau, L. F., and Duff, K. (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38, 555565,  DOI: 10.1016/S0896-6273(03)00259-9
  80. 80
    Piedrahita, D., Hernández, I., López-Tobón, A., Fedorov, D., Obara, B., Manjunath, B. S., Boudreau, R. L., Davidson, B., Laferla, F., Gallego-Gómez, J. C., Kosik, K. S., and Cardona-Gómez, G. P. (2010) Silencing of CDK5 reduces neurofibrillary tangles in transgenic alzheimer’s mice. J. Neurosci. 30, 1396613976,  DOI: 10.1523/JNEUROSCI.3637-10.2010
  81. 81
    Zheng, Y. L., Kesavapany, S., Gravell, M., Hamilton, R. S., Schubert, M., Amin, N., Albers, W., Grant, P., and Pant, H. C. (2005) A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons. EMBO J. 24, 209220,  DOI: 10.1038/sj.emboj.7600441
  82. 82
    Plattner, F., Angelo, M., and Giese, K. P. (2006) The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation. J. Biol. Chem. 281, 2545725465,  DOI: 10.1074/jbc.M603469200
  83. 83
    Li, T., Hawkes, C., Qureshi, H. Y., Kar, S., and Paudel, H. K. (2006) Cyclin-Dependent Protein Kinase 5 Primes Microtubule-Associated Protein Tau Site-Specifically for Glycogen Synthase Kinase 3β. Biochemistry 45, 31343145,  DOI: 10.1021/bi051635j
  84. 84
    Li, T. and Paudel, H. K. (2006) Glycogen Synthase Kinase 3β Phosphorylates Alzheimer’s Disease-Specific Ser396 of Microtubule-Associated Protein Tau by a Sequential Mechanism. Biochemistry 45, 31253133,  DOI: 10.1021/bi051634r
  85. 85
    Reinhardt, L., Kordes, S., Reinhardt, P., Glatza, M., Baumann, M., Drexler, H. C. A., Menninger, S., Zischinsky, G., Eickhoff, J., Fröb, C., Bhattarai, P., Arulmozhivarman, G., Marrone, L., Janosch, A., Adachi, K., Stehling, M., Anderson, E. N., Abo-Rady, M., Bickle, M., Pandey, U. B., Reimer, M. M., Kizil, C., Schöler, H. R., Nussbaumer, P., Klebl, B., and Sterneckert, J. L. (2019) Dual Inhibition of GSK3β and CDK5 Protects the Cytoskeleton of Neurons from Neuroinflammatory-Mediated Degeneration In Vitro and In Vivo. Stem Cell Rep. 12, 502517,  DOI: 10.1016/j.stemcr.2019.01.015
  86. 86
    Vassar, R., Kovacs, D. M., Yan, R., and Wong, P. C. (2009) The beta-secretase enzyme BACE in health and Alzheimer’s disease: regulation, cell biology, function, and therapeutic potential. J. Neurosci. 29, 1278712794,  DOI: 10.1523/JNEUROSCI.3657-09.2009
  87. 87
    Gu, L. and Guo, Z. (2013) Alzheimer’s Abeta42 and Abeta40 peptides form interlaced amyloid fibrils. J. Neurochem. 126, 305311,  DOI: 10.1111/jnc.12202
  88. 88
    Lopes, J. P., Oliveira, C. R., and Agostinho, P. (2007) Role of cyclin-dependent kinase 5 in the neurodegenerative process triggered by amyloid-Beta and prion peptides: implications for Alzheimer’s disease and prion-related encephalopathies. Cell. Mol. Neurobiol. 27, 943957,  DOI: 10.1007/s10571-007-9224-3
  89. 89
    Liu, L., Martin, R., Kohler, G., and Chan, C. (2013) Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes. Exp. Neurol. 248, 482490,  DOI: 10.1016/j.expneurol.2013.08.004
  90. 90
    Cruz, J. C., Kim, D., Moy, L. Y., Dobbin, M. M., Sun, X., Bronson, R. T., and Tsai, L.-H. (2006) p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. J. Neurosci. 26, 1053610541,  DOI: 10.1523/JNEUROSCI.3133-06.2006
  91. 91
    Wen, Y., Yu, W. H., Maloney, B., Bailey, J., Ma, J., Marié, I., Maurin, T., Wang, L., Figueroa, H., Herman, M., Krishnamurthy, P., Liu, L., Planel, E., Lau, L.-F., Lahiri, D. K., and Duff, K. (2008) Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron 57, 680690,  DOI: 10.1016/j.neuron.2008.02.024
  92. 92
    Liu, F., Su, Y., Li, B., Zhou, Y., Ryder, J., Gonzalez-DeWhitt, P., May, P. C., and Ni, B. (2003) Regulation of amyloid precursor protein (APP) phosphorylation and processing by p35/Cdk5 and p25/Cdk5. FEBS Lett. 547, 193196,  DOI: 10.1016/S0014-5793(03)00714-2
  93. 93
    Joshi, G., Bekier, M. E., 2nd, and Wang, Y. (2015) Golgi fragmentation in Alzheimer’s disease. Front. Neurosci. 9, 340,  DOI: 10.3389/fnins.2015.00340
  94. 94
    Joshi, G., Chi, Y., Huang, Z., and Wang, Y. (2014) Aβ-induced Golgi fragmentation in Alzheimer’s disease enhances Aβ production. Proc. Natl. Acad. Sci. U. S. A. 111, E12301239,  DOI: 10.1073/pnas.1320192111
  95. 95
    Erten-Lyons, D., Woltjer, R. L., Dodge, H., Nixon, R., Vorobik, R., Calvert, J. F., Leahy, M., Montine, T., and Kaye, J. (2009) Factors associated with resistance to dementia despite high Alzheimer disease pathology. Neurology 72, 354360,  DOI: 10.1212/01.wnl.0000341273.18141.64
  96. 96
    Sloane, J. A., Pietropaolo, M. F., Rosene, D. L., Moss, M. B., Peters, A., Kemper, T., and Abraham, C. R. (1997) Lack of correlation between plaque burden and cognition in the aged monkey. Acta Neuropathol. 94, 471478,  DOI: 10.1007/s004010050735
  97. 97
    Sengupta, U., Nilson, A. N., and Kayed, R. (2016) The Role of Amyloid-beta Oligomers in Toxicity, Propagation, and Immunotherapy. EBioMedicine 6, 4249,  DOI: 10.1016/j.ebiom.2016.03.035
  98. 98
    Han, X. J., Hu, Y. Y., Yang, Z. J., Jiang, L. P., Shi, S. L., Li, Y. R., Guo, M. Y., Wu, H. L., and Wan, Y. Y. (2017) Amyloid beta-42 induces neuronal apoptosis by targeting mitochondria. Mol. Med. Rep. 16, 45214528,  DOI: 10.3892/mmr.2017.7203
  99. 99
    Wilkaniec, A., Gąssowska-Dobrowolska, M., Strawski, M., Adamczyk, A., and Czapski, G. A. (2018) Inhibition of cyclin-dependent kinase 5 affects early neuroinflammatory signalling in murine model of amyloid beta toxicity. J. Neuroinflammation 15, 11,  DOI: 10.1186/s12974-017-1027-y
  100. 100
    Escribano, L., Simón, A.-M., Gimeno, E., Cuadrado-Tejedor, M., López de Maturana, R., García-Osta, A., Ricobaraza, A., Pérez-Mediavilla, A., Del Río, J., and Frechilla, D. (2010) Rosiglitazone rescues memory impairment in Alzheimer’s transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology 35, 15931604,  DOI: 10.1038/npp.2010.32
  101. 101
    Mehta, D., Jackson, R., Paul, G., Shi, J., and Sabbagh, M. (2017) Why do trials for Alzheimer’s disease drugs keep failing? A discontinued drug perspective for 2010–2015. Expert Opin. Invest. Drugs 26, 735739,  DOI: 10.1080/13543784.2017.1323868
  102. 102
    Knott, A. B., Perkins, G., Schwarzenbacher, R., and Bossy-Wetzel, E. (2008) Mitochondrial fragmentation in neurodegeneration. Nat. Rev. Neurosci. 9, 505518,  DOI: 10.1038/nrn2417
  103. 103
    Park, J., Choi, H., Min, J. S., Kim, B., Lee, S. R., Yun, J. W., Choi, M. S., Chang, K. T., and Lee, D. S. (2015) Loss of mitofusin 2 links beta-amyloid-mediated mitochondrial fragmentation and Cdk5-induced oxidative stress in neuron cells. J. Neurochem. 132, 687702,  DOI: 10.1111/jnc.12984
  104. 104
    Calkins, M. J., Manczak, M., Mao, P., Shirendeb, U., and Reddy, P. H. (2011) Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer’s disease. Hum. Mol. Genet. 20, 45154529,  DOI: 10.1093/hmg/ddr381
  105. 105
    Qu, D., Rashidian, J., Mount, M. P., Aleyasin, H., Parsanejad, M., Lira, A., Haque, E., Zhang, Y., Callaghan, S., Daigle, M., Rousseaux, M. W., Slack, R. S., Albert, P. R., Vincent, I., Woulfe, J. M., and Park, D. S. (2007) Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson’s disease. Neuron 55, 3752,  DOI: 10.1016/j.neuron.2007.05.033
  106. 106
    Dauer, W. and Przedborski, S. (2003) Parkinson’s disease: mechanisms and models. Neuron 39, 889909,  DOI: 10.1016/S0896-6273(03)00568-3
  107. 107
    Alvira, D., Ferrer, I., Gutierrez-Cuesta, J., Garcia-Castro, B., Pallas, M., and Camins, A. (2008) Activation of the calpain/cdk5/p25 pathway in the girus cinguli in Parkinson’s disease. Parkinsonism Relat Disord 14, 309313,  DOI: 10.1016/j.parkreldis.2007.09.005
  108. 108
    Brion, J. P. and Couck, A. M. (1995) Cortical and brainstem-type Lewy bodies are immunoreactive for the cyclin-dependent kinase 5. Am. J. Pathol. 147, 14651476
  109. 109
    Cardoso, S. M. (2011) The mitochondrial cascade hypothesis for Parkinson’s disease. Curr. Pharm. Des. 17, 33903397,  DOI: 10.2174/138161211798072508
  110. 110
    Exner, N., Lutz, A. K., Haass, C., and Winklhofer, K. F. (2012) Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J. 31, 30383062,  DOI: 10.1038/emboj.2012.170
  111. 111
    Larsen, S. B., Hanss, Z., and Krüger, R. (2018) The genetic architecture of mitochondrial dysfunction in Parkinson’s disease. Cell Tissue Res. 373, 2137,  DOI: 10.1007/s00441-017-2768-8
  112. 112
    Park, J., Seo, J., Won, J., Yeo, H. G., Ahn, Y. J., Kim, K., Jin, Y. B., Koo, B. S., Lim, K. S., Jeong, K. J., Kang, P., Lee, H. Y., Baek, S. H., Jeon, C. Y., Hong, J. J., Huh, J. W., Kim, Y. H., Park, S. J., Kim, S. U., Lee, D. S., Lee, S. R., and Lee, Y. (2019) Abnormal Mitochondria in a Non-human Primate Model of MPTP-induced Parkinson’s Disease: Drp1 and CDK5/p25 Signaling. Exp Neurobiol 28, 414424,  DOI: 10.5607/en.2019.28.3.414
  113. 113
    Bennett, M. C., Bishop, J. F., Leng, Y., Chock, P. B., Chase, T. N., and Mouradian, M. M. (1999) Degradation of alpha-synuclein by proteasome. J. Biol. Chem. 274, 3385533858,  DOI: 10.1074/jbc.274.48.33855
  114. 114
    Avraham, E., Rott, R., Liani, E., Szargel, R., and Engelender, S. (2007) Phosphorylation of Parkin by the Cyclin-dependent Kinase 5 at the Linker Region Modulates Its Ubiquitin-Ligase Activity and Aggregation. J. Biol. Chem. 282, 1284212850,  DOI: 10.1074/jbc.M608243200
  115. 115
    Hwang, O. (2013) Role of oxidative stress in Parkinson’s disease. Exp Neurobiol 22, 1117,  DOI: 10.5607/en.2013.22.1.11
  116. 116
    Smith, P. D., Mount, M. P., Shree, R., Callaghan, S., Slack, R. S., Anisman, H., Vincent, I., Wang, X., Mao, Z., and Park, D. S. (2006) Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2. J. Neurosci. 26, 440447,  DOI: 10.1523/JNEUROSCI.2875-05.2006
  117. 117
    Huang, E., Qu, D., Zhang, Y., Venderova, K., Haque, M. E., Rousseaux, M. W., Slack, R. S., Woulfe, J. M., and Park, D. S. (2010) The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death. Nat. Cell Biol. 12, 563571,  DOI: 10.1038/ncb2058
  118. 118
    Cerri, S. and Blandini, F. (2019) Role of Autophagy in Parkinson’s Disease. Curr. Med. Chem. 26, 37023718,  DOI: 10.2174/0929867325666180226094351
  119. 119
    Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T., and Sulzer, D. (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305, 12921295,  DOI: 10.1126/science.1101738
  120. 120
    Vogiatzi, T., Xilouri, M., Vekrellis, K., and Stefanis, L. (2008) Wild type alpha-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J. Biol. Chem. 283, 2354223556,  DOI: 10.1074/jbc.M801992200
  121. 121
    Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J.-i., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., and Tanaka, K. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880884,  DOI: 10.1038/nature04723
  122. 122
    Bredesen, D. E., Rao, R. V., and Mehlen, P. (2006) Cell death in the nervous system. Nature 443, 796802,  DOI: 10.1038/nature05293
  123. 123
    Wong, A. S. L., Lee, R. H. K., Cheung, A. Y., Yeung, P. K., Chung, S. K., Cheung, Z. H., and Ip, N. Y. (2011) Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease. Nat. Cell Biol. 13, 568,  DOI: 10.1038/ncb2217
  124. 124
    He, R., Huang, W., Huang, Y., Xu, M., Song, P., Huang, Y., Xie, H., and Hu, Y. (2018) Cdk5 Inhibitory Peptide Prevents Loss of Dopaminergic Neurons and Alleviates Behavioral Changes in an MPTP Induced Parkinson’s Disease Mouse Model. Front. Aging Neurosci. 10, 162,  DOI: 10.3389/fnagi.2018.00162
  125. 125
    Binukumar, B. K. and Pant, H. C. (2016) TFP5/TP5 peptide provides neuroprotection in the MPTP model of Parkinson’s disease. Neural Regener. Res. 11, 698701,  DOI: 10.4103/1673-5374.182681
  126. 126
    McColgan, P. and Tabrizi, S. J. (2018) Huntington’s disease: a clinical review. European Journal of Neurology 25, 2434,  DOI: 10.1111/ene.13413
  127. 127
    Wellington, C. L., Singaraja, R., Ellerby, L., Savill, J., Roy, S., Leavitt, B., Cattaneo, E., Hackam, A., Sharp, A., Thornberry, N., Nicholson, D. W., Bredesen, D. E., and Hayden, M. R. (2000) Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J. Biol. Chem. 275, 1983119838,  DOI: 10.1074/jbc.M001475200
  128. 128
    Liman, J., Deeg, S., Voigt, A., Vossfeldt, H., Dohm, C. P., Karch, A., Weishaupt, J., Schulz, J. B., Bahr, M., and Kermer, P. (2014) CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration. J. Neurochem. 129, 10131023,  DOI: 10.1111/jnc.12684
  129. 129
    Anne, S. L., Saudou, F., and Humbert, S. (2007) Phosphorylation of Huntingtin by Cyclin-Dependent Kinase 5 Is Induced by DNA Damage and Regulates Wild-Type and Mutant Huntingtin Toxicity in Neurons. J. Neurosci. 27, 7318,  DOI: 10.1523/JNEUROSCI.1831-07.2007
  130. 130
    Muchowski, P. J., Ning, K., D'Souza-Schorey, C., and Fields, S. (2002) Requirement of an intact microtubule cytoskeleton for aggregation and inclusion body formation by a mutant huntingtin fragment. Proc. Natl. Acad. Sci. U. S. A. 99, 727,  DOI: 10.1073/pnas.022628699
  131. 131
    Kaminosono, S., Saito, T., Oyama, F., Ohshima, T., Asada, A., Nagai, Y., Nukina, N., and Hisanaga, S.-i (2008) Suppression of Mutant Huntingtin Aggregate Formation by Cdk5/p35 through the Effect on Microtubule Stability. J. Neurosci. 28, 8747,  DOI: 10.1523/JNEUROSCI.0973-08.2008
  132. 132
    Paoletti, P., Vila, I., Rifé, M., Lizcano, J. M., Alberch, J., and Ginés, S. (2008) Dopaminergic and Glutamatergic Signaling Crosstalk in Huntington's Disease Neurodegeneration: The Role of p25/Cyclin-Dependent Kinase 5. J. Neurosci. 28, 10090,  DOI: 10.1523/JNEUROSCI.3237-08.2008
  133. 133
    Park, K. H. J., Lu, G., Fan, J., Raymond, L. A., and Leavitt, B. R. (2012) Decreasing Levels of the cdk5 Activators, p25 and p35, Reduces Excitotoxicity in Striatal Neurons. J. Huntington's Dis. 1, 8996,  DOI: 10.3233/JHD-2012-129000
  134. 134
    Chatterjee, A., Cutler, S. J., Doerksen, R. J., Khan, I. A., and Williamson, J. S. (2014) Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening. Bioorg. Med. Chem. 22, 64096421,  DOI: 10.1016/j.bmc.2014.09.043
  135. 135
    Dhavan, R. and Tsai, L. H. (2001) A decade of CDK5. Nat. Rev. Mol. Cell Biol. 2, 749759,  DOI: 10.1038/35096019
  136. 136
    Laha, J. K., Zhang, X., Qiao, L., Liu, M., Chatterjee, S., Robinson, S., Kosik, K. S., and Cuny, G. D. (2011) Structure-activity relationship study of 2,4-diaminothiazoles as Cdk5/p25 kinase inhibitors. Bioorg. Med. Chem. Lett. 21, 20982101,  DOI: 10.1016/j.bmcl.2011.01.140
  137. 137
    Meijer, L., Borgne, A., Mulner, O., Chong, J. P., Blow, J. J., Inagaki, N., Inagaki, M., Delcros, J. G., and Moulinoux, J. P. (1997) Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 243, 527536,  DOI: 10.1111/j.1432-1033.1997.t01-2-00527.x
  138. 138
    Lenjisa, J. L., Tadesse, S., Khair, N. Z., Kumarasiri, M., Yu, M., Albrecht, H., Milne, R., and Wang, S. (2017) CDK5 in oncology: recent advances and future prospects. Future Med. Chem. 9, 19391962,  DOI: 10.4155/fmc-2017-0097
  139. 139
    Khair, N. Z., Lenjisa, J. L., Tadesse, S., Kumarasiri, M., Basnet, S. K. C., Mekonnen, L. B., Li, M., Diab, S., Sykes, M. J., Albrecht, H., Milne, R., and Wang, S. (2019) Discovery of CDK5 Inhibitors through Structure-Guided Approach. ACS Med. Chem. Lett. 10, 786791,  DOI: 10.1021/acsmedchemlett.9b00029
  140. 140
    Cheung, Z. H. and Ip, N. Y. (2012) Cdk5: a multifaceted kinase in neurodegenerative diseases. Trends Cell Biol. 22, 169175,  DOI: 10.1016/j.tcb.2011.11.003
  141. 141
    Bhounsule, A. S., Bhatt, L. K., Prabhavalkar, K. S., and Oza, M. (2017) Cyclin dependent kinase 5: A novel avenue for Alzheimer’s disease. Brain Res. Bull. 132, 2838,  DOI: 10.1016/j.brainresbull.2017.05.006
  142. 142
    Xie, H., Wen, H., Zhang, D., Liu, L., Liu, B., Liu, Q., Jin, Q., Ke, K., Hu, M., and Chen, X. (2017) Designing of dual inhibitors for GSK-3beta and CDK5: Virtual screening and in vitro biological activities study. Oncotarget 8, 1811818128,  DOI: 10.18632/oncotarget.15085
  143. 143
    Helal, C. J., Sanner, M. A., Cooper, C. B., Gant, T., Adam, M., Lucas, J. C., Kang, Z., Kupchinsky, S., Ahlijanian, M. K., Tate, B., Menniti, F. S., Kelly, K., and Peterson, M. (2004) Discovery and SAR of 2-aminothiazole inhibitors of cyclin-dependent kinase 5/p25 as a potential treatment for Alzheimer’s disease. Bioorg. Med. Chem. Lett. 14, 55215525,  DOI: 10.1016/j.bmcl.2004.09.006
  144. 144
    Echalier, A., Hole, A. J., Lolli, G., Endicott, J. A., and Noble, M. E. (2014) An inhibitor’s-eye view of the ATP-binding site of CDKs in different regulatory states. ACS Chem. Biol. 9, 12511256,  DOI: 10.1021/cb500135f
  145. 145
    Liu, F., Liang, Z., Shi, J., Yin, D., El-Akkad, E., Grundke-Iqbal, I., Iqbal, K., and Gong, C. X. (2006) PKA modulates GSK-3beta- and cdk5-catalyzed phosphorylation of tau in site- and kinase-specific manners. FEBS Lett. 580, 62696274,  DOI: 10.1016/j.febslet.2006.10.033
  146. 146
    Zheng, Y. L., Li, B. S., Amin, N. D., Albers, W., and Pant, H. C. (2002) A peptide derived from cyclin-dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells. Eur. J. Biochem. 269, 44274434,  DOI: 10.1046/j.1432-1033.2002.03133.x
  147. 147
    Zheng, Y. L., Amin, N. D., Hu, Y. F., Rudrabhatla, P., Shukla, V., Kanungo, J., Kesavapany, S., Grant, P., Albers, W., and Pant, H. C. (2010) A 24-residue peptide (p5), derived from p35, the Cdk5 neuronal activator, specifically inhibits Cdk5–p25 hyperactivity and tau hyperphosphorylation. J. Biol. Chem. 285, 3420234212,  DOI: 10.1074/jbc.M110.134643
  148. 148
    Fisher, E., Pavlenko, K., Vlasov, A., and Ramenskaya, G. (2019) Peptide-Based Therapeutics for Oncology. Pharm. Med. 33, 920,  DOI: 10.1007/s40290-018-0261-7
  149. 149
    Peyressatre, M., Prevel, C., Pellerano, M., and Morris, M. C. (2015) Targeting cyclin-dependent kinases in human cancers: from small molecules to Peptide inhibitors. Cancers 7, 179237,  DOI: 10.3390/cancers7010179
  150. 150
    Corbel, C., Zhang, B., Le Parc, A., Baratte, B., Colas, P., Couturier, C., Kosik, K. S., Landrieu, I., Le Tilly, V., and Bach, S. (2015) Tamoxifen inhibits CDK5 kinase activity by interacting with p35/p25 and modulates the pattern of tau phosphorylation. Chem. Biol. 22, 472482,  DOI: 10.1016/j.chembiol.2015.03.009

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  38. Muriel Desbois, Karla J. Opperman, Jonathan Amezquita, Gabriel Gaglio, Oliver Crawley, Brock Grill, . Ubiquitin ligase activity inhibits Cdk5 to control axon termination. PLOS Genetics 2022, 18 (4) , e1010152. https://doi.org/10.1371/journal.pgen.1010152
  39. Stefania Demuro, Conall Sauvey, Shailesh K. Tripathi, Rita M.C. Di Martino, Da Shi, Jose A. Ortega, Debora Russo, Beatrice Balboni, Barbara Giabbai, Paola Storici, Stefania Girotto, Ruben Abagyan, Andrea Cavalli. ARN25068, a versatile starting point towards triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau-related neurological disorders. European Journal of Medicinal Chemistry 2022, 229 , 114054. https://doi.org/10.1016/j.ejmech.2021.114054
  40. Ana García-Osta, Jinya Dong, María Jesús Moreno-Aliaga, Maria Javier Ramirez. p27, The Cell Cycle and Alzheimer´s Disease. International Journal of Molecular Sciences 2022, 23 (3) , 1211. https://doi.org/10.3390/ijms23031211
  41. Soghra Bagheri, Ali Akbar Saboury. Kinase inhibition in Alzheimer’s disease. 2022, 505-533. https://doi.org/10.1016/B978-0-323-91287-7.00003-X
  42. Deeksha Tiwari, Nitish Mittal, Hem Chandra Jha. Unraveling the links between neurodegeneration and Epstein-Barr virus-mediated cell cycle dysregulation. Current Research in Neurobiology 2022, 3 , 100046. https://doi.org/10.1016/j.crneur.2022.100046
  43. Zahra Haghighijoo, Leila Zamani, Fatemeh Moosavi, Saeed Emami. Therapeutic potential of quinazoline derivatives for Alzheimer's disease: A comprehensive review. European Journal of Medicinal Chemistry 2022, 227 , 113949. https://doi.org/10.1016/j.ejmech.2021.113949
  44. Wei-Jia Zhi, Si-Mo Qiao, Yong Zou, Rui-Yun Peng, Hai-Tao Yan, Li-Zhen Ma, Ji Dong, Li Zhao, Bin-Wei Yao, Xue-Long Zhao, Xin-Xing Feng, Xiang-Jun Hu, Li-Feng Wang. Low p-SYN1 (Ser-553) Expression Leads to Abnormal Neurotransmitter Release of GABA Induced by Up-Regulated Cdk5 after Microwave Exposure: Insights on Protection and Treatment of Microwave-Induced Cognitive Dysfunction. Current Issues in Molecular Biology 2022, 44 (1) , 206-221. https://doi.org/10.3390/cimb44010015
  45. Bruna Schultz, Jéssica Taday, Leonardo Menezes, Anderson Cigerce, Marina C. Leite, Carlos-Alberto Gonçalves. Calpain-Mediated Alterations in Astrocytes Before and During Amyloid Chaos in Alzheimer’s Disease. Journal of Alzheimer's Disease 2021, 84 (4) , 1415-1430. https://doi.org/10.3233/JAD-215182
  46. Jyotirmoy Banerjee, Arpna Srivastava, Devina Sharma, Soumil Dey, Manjari Tripathi, M.C. Sharma, P Sarat Chandra, Aparna Banerjee Dixit. Differential regulation of excitatory synaptic transmission in the hippocampus and anterior temporal lobe by cyclin dependent kinase 5 (Cdk5) in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Neuroscience Letters 2021, 761 , 136096. https://doi.org/10.1016/j.neulet.2021.136096
  47. Nicole Mangold, Jeffrey Pippin, David Unnersjoe-Jess, Sybille Koehler, Stuart Shankland, Sebastian Brähler, Bernhard Schermer, Thomas Benzing, Paul T. Brinkkoetter, Henning Hagmann. The Atypical Cyclin-Dependent Kinase 5 (Cdk5) Guards Podocytes from Apoptosis in Glomerular Disease While Being Dispensable for Podocyte Development. Cells 2021, 10 (9) , 2464. https://doi.org/10.3390/cells10092464
  48. Lara Costa, Alessandra Tempio, Enza Lacivita, Marcello Leopoldo, Lucia Ciranna. Serotonin 5‐HT7 receptors require cyclin‐dependent kinase 5 to rescue hippocampal synaptic plasticity in a mouse model of Fragile X Syndrome. European Journal of Neuroscience 2021, 54 (1) , 4124-4132. https://doi.org/10.1111/ejn.15246
  49. Qinqin Zhao, Bei Zheng, Pinpin Feng, Xiang Li, . A Study to Decipher the Potential Effects of Butylphthalide against Central Nervous System Diseases Based on Network Pharmacology and Molecular Docking Integration Strategy. Evidence-Based Complementary and Alternative Medicine 2021, 2021 , 1-13. https://doi.org/10.1155/2021/6694698
  50. Kimberly Gomez, Tissiana G.M. Vallecillo, Aubin Moutal, Samantha Perez-Miller, Rodolfo Delgado-Lezama, Ricardo Felix, Rajesh Khanna. The role of cyclin-dependent kinase 5 in neuropathic pain. Pain 2020, 161 (12) , 2674-2689. https://doi.org/10.1097/j.pain.0000000000002027
  • Abstract

    Figure 1

    Figure 1. (A) Physiological condition: Cdk5 is chiefly activated by p35. Due to the ubiquitination signal held by the p10 fragment of p35, the Cdk5–p35 complex has a short half-life and is rapidly degraded by the proteasome. Cdk5 also autoinhibits its activity by phosphorylating and subsequently degrading p35. Cdk5 activity is limited to membrane targeting due to the myristoylation sequence present in the p10 fragment. (B) Pathological condition: Under pathological conditions, neurotoxic stimuli increase intracellular calcium levels that leads to the activation of calpain, a protease which cleaves the p10 fragment from p35 to produce p25. Losing the p10 fragment’s ubiquitination signal results in a significantly longer half-life for the Cdk5–p25 complex, leading to hyperactivation of Cdk5 and hyperphosphorylation of its physiological targets. Additionally, losing the myristoylation sequence allows Cdk5–p25 to relocate to the nucleus where it phosphorylates nonphysiological targets.

    Figure 2

    Figure 2. (A) For the postmitotic cells in the SVZ to begin radial migration along the glial fibers distributed throughout the cortex, they must first adopt a bipolar configuration. Cdk5 is required for the multipolar to bipolar transition and is responsible for the formation of the leading process. As each new cohort of neurons migrates, it must slide past the subplate and past previously deposited cell layers to reach its destination below the MZ. Cdk5–p35 facilitates this process by forming a complex with β-catenin, and subsequently with N-cadherin, to decrease N-cadherin mediated cell–cell adhesion. (B) PCs in the cerebellum primarily display radial migration to reach their final location in the PCL, while GCPs use tangential migration to reach their initial destination in the EGL. Cdk5 is required for the correct migration for both of these cell types, and PCs and GCPs lacking Cdk5 are located ectopically. The final inward migration of GCPs into the IGL is also reliant on Cdk5, and GCPs lacking Cdk5 remain in the EGL.

    Figure 3

    Figure 3. Aβ, derived from APP after cleavage by BACE and γ-secretase, induces calcium influx, activating calpain-mediated cleavage of p35 to p25. Cdk5 is hyperactivated by p25 that leads to hyperphosphorylation of Cdk5 targets. Cdk5–p25 and GSK3β, another tau kinase, work in concert to hyperphosphorylate tau, causing it to detach from MTs and aggregate to form PHFs and NFTs within the neuron. The NFTs and destabilized MTs impair axonal transport, disrupt intracellular communication, and cause neuronal death. Cdk5–p25 directly and indirectly increases Aβ production. Cdk5–p25 directly phosphorylates APP leading to increased Aβ production. Cdk5–p25 phosphorylates STAT3, causing increased BACE activity and transcription leading to increased cleavage of APP. Additionally, Cdk5–p25 induces Golgi fragmentation by phosphorylating Golgi tethering protein GM130, which interacts with the Golgi structural protein, GRASP 65, causing aberrant processing of APP. Aβ instigates mitochondrial fragmentation by increasing mitochondrial fission and Cdk5–p25 reduces the activity of Px2 to cause excessive accumulation of ROS, leading to oxidative stress and neuronal death. Excessive ROS disrupts intracellular calcium levels, further dysregulating Cdk5 activity.

    Figure 4

    Figure 4. Mechanisms contributing to the loss of dopaminergic neurons in PD include mitochondrial dysfunction, oxidative stress, as well as aberrant autophagy and impaired protein clearance pathways. Cdk5 contributes to the pathogenesis of PD by phosphorylating key proteins, such as Ape1, Drp1, Px2, Parkin, MEF2, and EndoB1 that are involved in the aforementioned processes.

    Figure 5

    Figure 5. Therapeutic strategies toward inhibiting pathological Cdk5 activity. (A) Nonselective: Small molecules that compete for the active ATP binding site within the kinase domain. (B) Selective: Disruption of protein–Cdk interaction using peptides. (C) Selective: Disruption of protein–Cdk interaction using small molecule inhibitors.

  • References

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    Jump To

    This article references 150 other publications.

    1. 1
      Malumbres, M., Harlow, E., Hunt, T., Hunter, T., Lahti, J. M., Manning, G., Morgan, D. O., Tsai, L. H., and Wolgemuth, D. J. (2009) Cyclin-dependent kinases: a family portrait. Nat. Cell Biol. 11, 12751276,  DOI: 10.1038/ncb1109-1275
    2. 2
      Malumbres, M. (2014) Cyclin-dependent kinases. Genome Biol. 15, 122,  DOI: 10.1186/gb4184
    3. 3
      Lee, M. G. and Nurse, P. (1987) Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2. Nature 327, 3135,  DOI: 10.1038/327031a0
    4. 4
      Andzelm, E. R., Lew, J., and Taylor, S. (1995) Bound to activate: conformational consequences of cyclin binding to CDK2. Structure 3, 11351141,  DOI: 10.1016/S0969-2126(01)00249-0
    5. 5
      Xiong, Y., Zhang, H., and Beach, D. (1992) D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 71, 505514,  DOI: 10.1016/0092-8674(92)90518-H
    6. 6
      Ishiguro, K., Takamatsu, M., Tomizawa, K., Omori, A., Takahashi, M., Arioka, M., Uchida, T., and Imahori, K. (1992) Tau protein kinase I converts normal tau protein into A68-like component of paired helical filaments. J. Biol. Chem. 267, 1089710901
    7. 7
      Hellmich, M. R., Pant, H. C., Wada, E., and Battey, J. F. (1992) Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc. Natl. Acad. Sci. U. S. A. 89, 1086710871,  DOI: 10.1073/pnas.89.22.10867
    8. 8
      Cruz, J. C., Tseng, H. C., Goldman, J. A., Shih, H., and Tsai, L. H. (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40, 471483,  DOI: 10.1016/S0896-6273(03)00627-5
    9. 9
      Lopes, J. P. and Agostinho, P. (2011) Cdk5: multitasking between physiological and pathological conditions. Prog. Neurobiol. 94, 4963,  DOI: 10.1016/j.pneurobio.2011.03.006
    10. 10
      Zhang, J., Li, H., Yabut, O., Fitzpatrick, H., D’Arcangelo, G., and Herrup, K. (2010) Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex. J. Neurosci. 30, 52195228,  DOI: 10.1523/JNEUROSCI.5628-09.2010
    11. 11
      Kim, D., Frank, C. L., Dobbin, M. M., Tsunemoto, R. K., Tu, W., Peng, P. L., Guan, J. S., Lee, B. H., Moy, L. Y., Giusti, P., Broodie, N., Mazitschek, R., Delalle, I., Haggarty, S. J., Neve, R. L., Lu, Y., and Tsai, L. H. (2008) Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 60, 803817,  DOI: 10.1016/j.neuron.2008.10.015
    12. 12
      Chang, K. H., Vincent, F., and Shah, K. (2012) Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death. J. Cell Sci. 125, 51245137,  DOI: 10.1242/jcs.108183
    13. 13
      Tarricone, C., Dhavan, R., Peng, J., Areces, L. B., Tsai, L. H., and Musacchio, A. (2001) Structure and regulation of the CDK5-p25(nck5a) complex. Mol. Cell 8, 657669,  DOI: 10.1016/S1097-2765(01)00343-4
    14. 14
      Patrick, G. N., Zukerberg, L., Nikolic, M., de la Monte, S., Dikkes, P., and Tsai, L. H. (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615622,  DOI: 10.1038/45159
    15. 15
      Wilkaniec, A., Czapski, G. A., and Adamczyk, A. (2016) Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses. J. Neurochem. 136, 222233,  DOI: 10.1111/jnc.13365
    16. 16
      Sun, K. H., de Pablo, Y., Vincent, F., and Shah, K. (2008) Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction. J. Neurochem. 107, 265278,  DOI: 10.1111/j.1471-4159.2008.05616.x
    17. 17
      Chang, K. H., Multani, P. S., Sun, K. H., Vincent, F., de Pablo, Y., Ghosh, S., Gupta, R., Lee, H. P., Lee, H. G., Smith, M. A., and Shah, K. (2011) Nuclear envelope dispersion triggered by deregulated Cdk5 precedes neuronal death. Mol. Biol. Cell 22, 14521462,  DOI: 10.1091/mbc.e10-07-0654
    18. 18
      Sun, K. H., de Pablo, Y., Vincent, F., Johnson, E. O., Chavers, A. K., and Shah, K. (2008) Novel genetic tools reveal Cdk5′s major role in Golgi fragmentation in Alzheimer’s disease. Mol. Biol. Cell 19, 30523069,  DOI: 10.1091/mbc.e07-11-1106
    19. 19
      Smith, P. D., Crocker, S. J., Jackson-Lewis, V., Jordan-Sciutto, K. L., Hayley, S., Mount, M. P., O’Hare, M. J., Callaghan, S., Slack, R. S., Przedborski, S., Anisman, H., and Park, D. S. (2003) Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease. Proc. Natl. Acad. Sci. U. S. A. 100, 1365013655,  DOI: 10.1073/pnas.2232515100
    20. 20
      Luo, S., Vacher, C., Davies, J. E., and Rubinsztein, D. C. (2005) Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J. Cell Biol. 169, 647656,  DOI: 10.1083/jcb.200412071
    21. 21
      Liebl, J., Fürst, R., Vollmar, A. M., and Zahler, S. (2011) Twice switched at birth: cell cycle-independent roles of the ″neuron-specific″ cyclin-dependent kinase 5 (Cdk5) in non-neuronal cells. Cell. Signalling 23, 16981707,  DOI: 10.1016/j.cellsig.2011.06.020
    22. 22
      Pozo, K. and Bibb, J. A. (2016) The Emerging Role of Cdk5 in Cancer. Trends Cancer 2, 606618,  DOI: 10.1016/j.trecan.2016.09.001
    23. 23
      Shetty, K. T., Link, W. T., and Pant, H. C. (1993) cdc2-like kinase from rat spinal cord specifically phosphorylates KSPXK motifs in neurofilament proteins: isolation and characterization. Proc. Natl. Acad. Sci. U. S. A. 90, 68446848,  DOI: 10.1073/pnas.90.14.6844
    24. 24
      Beaudette, K. N., Lew, J., and Wang, J. H. (1993) Substrate specificity characterization of a cdc2-like protein kinase purified from bovine brain. J. Biol. Chem. 268, 2082520830