Cdk5: a multifaceted kinase in neurodegenerative diseases

Cheung, Zelda H.; Ip, Nancy Y.

doi:10.1016/j.tcb.2011.11.003

Cited by 208 publications

(156 citation statements)

References 77 publications

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“…Cdk5 is known to be deregulated in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), which causes neurotoxicity. Consequently, although the deregulation of other Cdks commonly occurs in many types of cancer, Cdk5 is emerging as a potential clinical target to treat multiple neurodegenerative diseases (Cheung and Ip, 2012). Thus, Cdk5 is unique among the Cdks in that it employs its own activation strategies, and has widely diverse functions in neuronal and nonneuronal tissues with different clinical implications (Hisanaga and Endo, 2010).…”

Section: Introductionmentioning

confidence: 99%

Cdk5 activity in the brain – multiple paths of regulation

Shah

Lahiri

2014

Journal of Cell Science

169

126

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Cyclin dependent kinase-5 (Cdk5), a family member of the cyclindependent kinases, plays a pivotal role in the central nervous system. During embryogenesis, Cdk5 is indispensable for brain development and, in the adult brain, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation. However, Cdk5 activity becomes deregulated in several neurological disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, which leads to neurotoxicity. Therefore, precise control over Cdk5 activity is essential for its physiological functions. This Commentary covers the various mechanisms of Cdk5 regulation, including several recently identified protein activators and inhibitors of Cdk5 that control its activity in normal and diseased brains. We also discuss the autoregulatory activity of Cdk5 and its regulation at the transcriptional, post-transcriptional and post-translational levels. We finally highlight physiological and pathological roles of Cdk5 in the brain. Specific modulation of these protein regulators is expected to provide alternative strategies for the development of effective therapeutic interventions that are triggered by deregulation of Cdk5.

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Section: Introductionmentioning

confidence: 99%

Cdk5 activity in the brain – multiple paths of regulation

Shah

Lahiri

2014

Journal of Cell Science

169

126

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“…In support of its role in the pathogenesis of AD, the activity of Cdk5 is upregulated in AD patient's brain (Wen et al, 2008). Activation of Cdk5 increases while inhibiting Cdk5 activity attenuates A generation (Cheung and Ip, 2012).…”

Section: Introductionmentioning

confidence: 97%

P3–076: Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes

Liu

Martin

Kohler

et al. 2013

Alzheimer's & Dementia

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Deregulation of calcium has been implicated in neurodegenerative diseases, including Alzheimer's disease (AD). Previously, we showed that saturated free-fatty acid, palmitate, causes AD-like changes in primary cortical neurons mediated by astrocytes. However, the molecular mechanisms by which conditioned media from astrocytes cultured in palmitate induces AD-like changes in neurons are unknown. This study demonstrates that this condition media from astrocytes elevates calcium level in the neurons, which subsequently increases calpain activity, a calcium-dependent protease, leading to enhance p25/Cdk5 activity and phosphorylation and activation of the STAT3 (signal transducer and activator of transcription) transcription factor. Inhibiting calpain or Cdk5 significantly reduces the upregulation in nuclear level of pSTAT3, which we found to transcriptionally regulate both BACE1 and presenilin-1, the latter is a catalytic subunit ofsecretase. Decreasing pSTAT3 levels reduced the mRNA levels of both BACE1 and presenilin-1 to near control levels. These data demonstrate a signal pathway leading to the activation of STAT3, and the generation of the amyloid peptide. Thus, our results suggest that STAT3 is an important potential therapeutic target of AD pathogenesis.

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“…5 Therefore, dysregulation of Cdk5 activity has been linked to an array of neurodegenerative diseases. 2,5,6 Consequently, Cdk5-mediated phosphorylation of several key intracellular substrates has received significant attention and has been identified to associate with the pathophysiology of neurodegeneration. 6,7 Recently, our laboratory made an attempt to identify the novel substrate of Cdk5 and we came across that Cdk5 interacts with C-terminus of Hsc70-interacting protein (CHIP).…”

mentioning

confidence: 99%

“…2,5,6 Consequently, Cdk5-mediated phosphorylation of several key intracellular substrates has received significant attention and has been identified to associate with the pathophysiology of neurodegeneration. 6,7 Recently, our laboratory made an attempt to identify the novel substrate of Cdk5 and we came across that Cdk5 interacts with C-terminus of Hsc70-interacting protein (CHIP). CHIP is composed of three major domains: (1) an aminoterminal three tetratricopeptide repeat (TPR) domain interacting with Hsc/Hsp70 and Hsp90, (2) a highly charged central domain with unknown functions and (3) a carboxyl-terminal U-box domain conferring E3 ubiquitin ligase activity.…”

mentioning

confidence: 99%

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

et al. 2015

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Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase and its dysregulation is implicated in neurodegenerative diseases. Likewise, C-terminus of Hsc70-interacting protein (CHIP) is linked to neurological disorders, serving as an E3 ubiquitin ligase for targeting damaged or toxic proteins for proteasomal degradation. Here, we demonstrate that CHIP is a novel substrate for Cdk5. Cdk5 phosphorylates CHIP at Ser20 via direct binding to a highly charged domain of CHIP. Co-immunoprecipitation and ubiquitination assays reveal that Cdk5-mediated phosphorylation disrupts the interaction between CHIP and truncated apoptosis-inducing factor (tAIF) without affecting CHIP's E3 ligase activity, resulting in the inhibition of CHIPmediated degradation of tAIF. Lentiviral transduction assay shows that knockdown of Cdk5 or overexpression of CHIP S20A , but not CHIP WT , attenuates tAIF-mediated neuronal cell death induced by hydrogen peroxide. Thus, we conclude that Cdk5-mediated phosphorylation of CHIP negatively regulates its neuroprotective function, thereby contributing to neuronal cell death progression following neurotoxic stimuli.

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Cdk5: a multifaceted kinase in neurodegenerative diseases

Cited by 208 publications

References 77 publications

Cdk5 activity in the brain – multiple paths of regulation

Cdk5 activity in the brain – multiple paths of regulation

P3–076: Palmitate induces transcriptional regulation of BACE1 and presenilin by STAT3 in neurons mediated by astrocytes

Phosphorylation of CHIP at Ser20 by Cdk5 promotes tAIF-mediated neuronal death

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