Cdk5: A main culprit in neurodegeneration

Gupta, Krishna Kant

doi:10.1080/00207454.2019.1645142

Cited by 19 publications

(13 citation statements)

References 68 publications

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“…Interestingly, recent studies have described that like GSK3 and p38 MAPK, CDK5 also inhibits autophagy although acting through a different mechanism involving phosphorylation of the Vps34 protein which interferes with its interaction with Beclin-1, an interaction required for the initiation of autophagy. Besides affecting clearance of pathogenic Aβ and Tau, one study has shown that CDK-mediated inhibition of autophagy deregulates APP processing [ 204 , 210 , 211 ].…”

Section: The Enzymesmentioning

confidence: 99%

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When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

D’Mello¹

2021

IJMS

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Alzheimer’s disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington’s disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.

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Section: The Enzymesmentioning

confidence: 99%

“…CDK5 is also a major Tau kinase and causes Tau dysfunction [ 209 ]. Through phosphorylation of Vps35, CDK inhibits autophagic clearance of Aβ and Tau [ 204 , 210 , 211 ]. CDK5 produces neuroinflammation both by promoting neuronal death and more directly by stimulating lysophosphatidylcholine release from glia [ 212 ].…”

Section: Figurementioning

confidence: 99%

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

D’Mello¹

2021

IJMS

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“…p35 (NCK5a, neuronal CDK5 activator) was first discovered due to its association and activation of CDK5 [17][18][19]. However, p39 (NCK5ai, neuronal CDK5 activator isoform) was first identified as a 39 kDa isoform of p35 that shared 57% amino acid homology with p35 [20], p25 was first discovered as a truncated form of p35 that was found in the neurons of Alzheimer patients [21], and subsequent studies identified that cleavage of p35 into p25 was calpain-and dephosphorylation-dependent [22][23][24]. Lastly, p29, a similarly cleaved product of p39, has also been identified and is known to play a role in the deregulation of CDK5 [25].…”

Section: Activators Of Cdk5mentioning

confidence: 99%

“…Lastly, the cleaved products of p35/p39, p25/p29 respectively, are protected from degradation as they lack the N-terminal p10 region. This leads to aberrant subcellular localization and interaction of p25/p29 with CDK5, which results in deregulation of CDK5 target specificity and promotes neurodegeneration [23,53,54].…”

Section: Regulation Of Cdk5 Activitymentioning

confidence: 99%

“…Its function is indispensable for proper neuronal migration and differentiation, axonal elongation, and synaptic function. Also, association of CDK5 with p25 leads to altered regulation of CDK5 that promotes neuronal apoptosis and development of neurological diseases such as Alzheimer's and Parkinson's disease [1,23,36,40,53,68,69]. Studies of CDK5 −/− and p35/p39 −/− mice have revealed that these mice die during the perinatal period of development due to widespread disruption of neuronal migration in the cerebral cortex, hippocampus, and cerebellum, resulting in a lack of cortical laminar structure and cerebellar foliation [12,53,68,70,71].…”

Section: Function Of Cdk5 In Neuronal Developmentmentioning

confidence: 99%

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CDK5: Key Regulator of Apoptosis and Cell Survival

Roufayel

Murshid

2019

Biomedicines

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The atypical cyclin-dependent kinase 5 (CDK5) is considered as a neuron-specific kinase that plays important roles in many cellular functions including cell motility and survival. The activation of CDK5 is dependent on interaction with its activator p35, p39, or p25. These activators share a CDK5-binding domain and form a tertiary structure similar to that of cyclins. Upon activation, CDK5/p35 complexes localize primarily in the plasma membrane, cytosol, and perinuclear region. Although other CDKs are activated by cyclins, binding of cyclin D and E showed no effect on CDK5 activation. However, it has been shown that CDK5 can be activated by cyclin I, which results in anti-apoptotic functions due to the increased expression of Bcl-2 family proteins. Treatment with the CDK5 inhibitor roscovitine sensitizes cells to heat-induced apoptosis and its phosphorylation, which results in prevention of the apoptotic protein functions. Here, we highlight the regulatory mechanisms of CDK5 and its roles in cellular processes such as gene regulation, cell survival, and apoptosis.

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Comprehensive analysis of CDK5 as a novel biomarker for progression in esophageal cancer

Ling

Sheng

et al. 2023

Esophagus

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Cdk5: A main culprit in neurodegeneration

Cited by 19 publications

References 68 publications

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer’s and Huntington’s Disease

CDK5: Key Regulator of Apoptosis and Cell Survival

Comprehensive analysis of CDK5 as a novel biomarker for progression in esophageal cancer

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