Cdk5 is essential for synaptic vesicle endocytosis

Tan, Timothy C.; Valova, Valentina A.; Malladi, Chandra S.; Graham, Mark E.; Berven, Leise A.; Jupp, Orla J.; Hansra, Gurdip; McClure, Sonya J.; Šarčević, Boris; Boadle, Ross; Larsen, Martin R.; Cousin, Michael A.; Robinson, Phillip J.

doi:10.1038/ncb1020

Cited by 282 publications

(384 citation statements)

References 51 publications

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“…28,29 In addition, CDK5 has previously been shown to be implicated in various cellular events involving turnover of biological membranes, for example cell migration, axonal outgrowth or endocytosis. 10,27,11 These cellular functions also require cytoskelettal structures, and we considered that, albeit a simplifying view, the process of mitochondrial fission shares mechanistic similarities with the cleavage of cell membranes during 'pinching off' of endocytotic vesicles.…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, CDK5 has previously been demonstrated to play a critical role in synaptic vesicle endocytosis by phosphorylation of dynamin 1. 11 Similarly, the dynaminrelated protein 1 (Drp1) may be directly modulated by CDK5. However, CDK5 could also indirectly regulate Drp1 function or localization by phosphorylation of one or several other CDK5 substrates, for example via cytoskeletal alterations.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it is involved in neuronspecific functions including, for example, synaptic plasticity, axonal outgrowth or transmitter release. [8][9][10][11] In neurological diseases, deregulated CDK5 turned out to be an apical instigator of neuronal cell death cascades. Amyloid-toxicity was shown to induce calpain-mediated cleavage of the CDK5 activators p35 or p39 to p25 and p29.…”

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Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis

et al. 2007

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Under physiological conditions, mitochondrial morphology dynamically shifts between a punctuate appearance and tubular networks. However, little is known about upstream signal transduction pathways that regulate mitochondrial morphology. We show that mitochondrial fission is a very early and kinetically invariant event during neuronal cell death, which causally contributes to cytochrome c release and neuronal apoptosis. Using a small molecule CDK5 inhibitor, as well as a dominantnegative CDK5 mutant and RNAi knockdown experiments, we identified CDK5 as an upstream signalling kinase that regulates mitochondrial fission during apoptosis of neurons. Vice versa, our study shows that mitochondrial fission is a modulator contributing to CDK5-mediated neurotoxicity. Thereby, we provide a link that allows integration of CDK5 into established neuronal apoptosis pathways. Mitochondria can acquire a broad range of morphologies, from a punctuate shape to a tubular appearance or even extended networks. Several proteins, most of them belonging to the family of large GTPases, have been identified that energy-dependently regulate mitochondrial morphology and subcellular distribution by promoting either fission (Fis1, dynamin-related protein 1 (Drp1), MTP18) or fusion of mitochondria (Mfn1/2 and Opa1). 1-3 As a potential upstream regulatory factor, the actin cytoskeleton has been shown to be a prerequisite for mitochondrial fission, possibly by its influence on Drp1 recruitment to mitochondria. 4 Apoptotic release of the mitochondrial cytochrome c and other proapoptotic mitochondrial proteins results in formation of the so-called apoptosome, which in turn activates downstream effector caspases with death executing function. 5 This intrinsic, mitochondrial death pathway is relevant for most forms of neuronal apoptosis, in contrast to extrinsic, for example death receptor mediated, activation of programmed cell death. 6 However, despite the contribution of mitochondrial dysfunction specifically to the demise of neurons, there is only scarce knowledge about mitochondrial fission during neuronal apoptosis, nor about its functional contribution to neuronal cell death. Furthermore, little is known about upstream regulatory pathways for mitochondrial morphology in general.Cyclin-dependent kinase 5 (CDK5) is a member of the CDK family, but, distinct from other CDKs, it does not participate in cell cycle regulation. 7 Instead, CDK5 is physiologically implicated in cytoskeletal functions, as well as regulation of membrane turnover and morphology, for example cell migration or endocytosis. Moreover, it is involved in neuronspecific functions including, for example, synaptic plasticity, axonal outgrowth or transmitter release. [8][9][10][11] In neurological diseases, deregulated CDK5 turned out to be an apical instigator of neuronal cell death cascades. Amyloid-toxicity was shown to induce calpain-mediated cleavage of the CDK5 activators p35 or p39 to p25 and p29. This leads to redistribution and overactivation of CDK5 after its association...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis

et al. 2007

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“…In addition to its established role in regulating the actin cytoskeleton, Rac1⅐GTP also interacts with p35/cdk5 kinase (109). Although the functional significance of this interaction is not clearly understood, p35/cdk5 is required for neurite outgrowth (110) and synaptic vesicle endocytosis (111), implicating a role for Rac1⅐GTP in both of these processes. Additionally, although it is well appreciated that phosphatidylinositides activate Rac1 through direct interaction with the PH domain of Rac1 GEFs, recent evidence has been presented that shows Rac1⅐GTP can positively regulate phosphatidylinositide production through its interaction with phosphatidylinositol 3-kinase (112).…”

Section: Discussionmentioning

confidence: 99%

Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor

Topp

Gray

Gerard

et al. 2004

Journal of Biological Chemistry

170

156

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ALS2 is the gene mutated in a recessive juvenile form of amyotrophic lateral sclerosis (ALS2). ALS2 encodes a large protein termed alsin, which contains a number of predicted cell signaling and protein trafficking sequence motifs. To gain insight into the overall function of alsin and to begin to evaluate its role in motor neuron maintenance, we examined the subcellular localization of alsin and the biochemical activities associated with its individual subdomains. We found that the Vps9p domain of alsin has Rab5 guanine nucleotide exchange activity. In addition, alsin interacted specifically with and acted as a guanine nucleotide exchange factor for Rac1. Immunofluorescence and fractionation experiments in both fibroblasts and neurons revealed that alsin is a cytosolic protein, with a significant portion associated with small, punctate membrane structures. Many of these membrane structures also contained Rab5 or Rac1. Upon overexpression of full-length alsin, the overexpressed material was largely cytosolic, indicating that the association with membrane structures could be saturated. We also found that alsin was present in membrane ruffles and lamellipodia. These data suggest that alsin is involved in membrane transport events, potentially linking endocytic processes and actin cytoskeleton remodeling.Amyotrophic lateral sclerosis (ALS) 1 is a heterogeneous neurological disorder characterized by progressive degeneration of motor neurons, usually causing death as a result of respiratory paralysis (1, 2). Although mostly sporadic in nature, a genetic link has been established in 5-10% of ALS cases (3). Chromosomal mapping studies have identified six independent loci associated with the familial forms of ALS (Refs. 4 -10; reviewed in Refs. 11 and 12). Molecular genetic analysis identified two genes that, when mutated, lead to ALS. The first discovered was the gene coding for Cu-Zn superoxide dismutase 1 (SOD1) (10). Initially, mutations in SOD1 were thought to result in defective free radical scavenger activity. However, it is now generally accepted that the alterations in SOD1 that lead to ALS are the result of an unknown, but toxic gain-of-function. The second gene identified is mutated in a juvenile form of ALS, ALS2 (13,14). Mutations in this gene lead to a rare recessive form of ALS that presents early in life and progresses much more slowly than the classical form (6, 15). Two small deletions in ALS2 were originally associated with the disease (13,14). Each is expected to severely truncate the predicted protein product of ALS2. In addition, mutations in ALS2 have recently been associated with two other neurodegenerative disorders, juvenile-onset primary lateral sclerosis (14) and infantile-onset hereditary spastic paralegia (16 -18). Like the original mutations identified, these mutations are predicted to generate prematurely truncated forms of the protein product.The protein encoded by ALS2, alsin, is predicted to contain numerous domains implicating roles in cell signaling, membrane localization, and protein...

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“…While earlier studies focused on the role of Cdk5 in brain development, more recent work has implicated Cdk5 in synaptic transmission in mature neurons. Presynaptically, Cdk5 has been suggested to regulate neurotransmitter release and synaptic vesicle endocytosis through the phosphorylation of synapsin I (Matsubara et al, 1996), the α-subunit of the P/Q-type voltage-dependent Ca 2+ channel (Tomizawa et al, 2002), amphiphysin I (Floyd et al, 2001), dynamin I (Tan et al, 2003;Tomizawa et al, 2003), and synaptojanin I (Lee et al, 2004). In the postsynaptic compartment, Cdk5 modulates synaptic plasticity (Hawasli et al, 2007) and phosphorylates the NR2A subunit of the Nmethyl-D-aspartate-type glutamate receptor Wang et al, 2003), the postsynaptic density protein, PSD-95 (Morabito et al, 2004), and the protein phosphatase-1 inhibitors, inhibitor-1 ) and its striatal homolog, the dopamine-and cAMPregulated phosphoprotein, M r 32,000 (DARPP-32) (Bibb et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Negative regulation of cyclin-dependent kinase 5 targets by protein kinase C

Sahin

Hawasli

Greene³

et al. 2008

European Journal of Pharmacology

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Cyclin-dependent kinase 5 (Cdk5) is a proline-directed protein serine/threonine kinase essential for brain development and implicated in synaptic plasticity, dopaminergic neurotransmission, drug addiction, and neurodegenerative disorders. Relatively little is known about the molecular mechanisms that regulate the activity of Cdk5 in vivo. In order to determine whether protein kinase C (PKC) regulates Cdk5 activity in the central nervous system, the phosphorylation levels of two Cdk5 substrates were evaluated under conditions of altered PKC activity in vivo. Treatment of acute striatal slices with a PKC-activating phorbol ester caused a time-and dose-dependent decrease in the levels of phospho-Ser6 inhibitor-1, phospho-Ser67 inhibitor-1, and phospho-Thr75 dopamine-and cAMP-regulated phosphoprotein, M r 32,000 (DARPP-32). This effect was reversed by the PKC inhibitor, Ro-32-0432. Moreover, phospho-Ser6 inhibitor-1, phospho-Ser67 inhibitor-1, and phospho-Thr75 DARPP-32 levels were elevated in brain tissue from mice lacking the gene for PKC-α. PKC did not phosphorylate Cdk5 or its cofactor, p25, in vitro. Striatal levels of the Cdk5 cofactor, p35, did not change in response to phorbol ester treatment. Furthermore, Cdk5 immunoprecipitated from striatal slices treated with phorbol ester had unaltered activity toward a control substrate in vitro. These results suggest that PKC exerts its effects on the phosphorylation state of Cdk5 substrates through an indirect mechanism that may involve the regulatory binding partners of Cdk5 other than its neuronal cofactors.

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Cdk5 is essential for synaptic vesicle endocytosis

Cited by 282 publications

References 51 publications

Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis

Cyclin-dependent kinase 5 is an upstream regulator of mitochondrial fission during neuronal apoptosis

Alsin Is a Rab5 and Rac1 Guanine Nucleotide Exchange Factor

Negative regulation of cyclin-dependent kinase 5 targets by protein kinase C

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