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Tale of the Good and the Bad Cdk5: Remodeling of the Actin Cytoskeleton in the Brain

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Abstract

Cdk5 kinase, a cyclin-dependent kinase family member, is a key regulator of cytoskeletal remodeling in the brain. Cdk5 is essential for brain development during embryogenesis. After birth, it is essential for numerous neuronal processes such as learning and memory formation, drug addiction, pain signaling, and long-term behavior changes, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity is deregulated in various brain disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and ischemic stroke, resulting in profound remodeling of the neuronal cytoskeleton, loss of synapses, and ultimately neurodegeneration. This review focuses on the “good and bad” Cdk5 in the brain and its pleiotropic contribution in regulating neuronal actin cytoskeletal remodeling. A vast majority of physiological and pathological Cdk5 substrates are associated with the actin cytoskeleton. Thus, our special emphasis is on the numerous Cdk5 substrates identified in the past two decades such as ephexin1, p27, Mst3, CaMKv, kalirin-7, RasGRF2, Pak1, WAVE1, neurabin-1, TrkB, 5-HT6R, talin, drebrin, synapsin I, synapsin III, CRMP1, GKAP, SPAR, PSD-95, and LRRK2. These substrates have unraveled the molecular mechanisms by which Cdk5 plays divergent roles in regulating neuronal actin cytoskeletal dynamics both in healthy and diseased states.

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Abbreviations

Aβ:

β-Amyloid

CAK:

Cdk-activating kinase

CaMKv:

Calmodulin kinase-like vesicle-associated

Cdk:

Cyclin-dependent kinase

Cdk1:

Cyclin-dependent kinase-1

Cdk2:

Cyclin-dependent kinase-2

Cdk5:

Cyclin-dependent kinase-5

CKI:

Cdk inhibitor protein

CRMP1:

Collapsin response mediator protein-1

EphA:

Ephrin receptor A

GAP:

GTPase-activating protein

GEF:

Guanine nucleotide exchange factor

GSTP1:

Glutathione S-transferase pi 1

5-HT6R:

5-Hydroxytryptamine-6 receptor

LIMK:

LIM kinase

LTD:

Long-term depression

LTP:

Long-term potentiation

MLCK:

Myosin light-chain kinase

MT:

Microtubule

Myt1:

Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase isoform 1

NMDA:

N-Methyl-d-aspartate

NMDAR:

N-Methyl-d-aspartate receptor

Pak1:

p21 activated kinase

p21Cip1:

Cyclin-dependent kinase inhibitor 1A

p27Kip1:

Cyclin-dependent kinase inhibitor 1B

PD:

Parkinson’s disease

TrkB:

Tropomyosin receptor kinase B

VGCC:

Voltage-gated calcium channels

WAVE1:

Wiskott-Aldrich syndrome protein (WASP)-family verprolin homologous protein 1

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Acknowledgments

This work was supported by a grant from the National Institutes of Health (NIAR21AG 47447) to KS.

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  1. Department of Chemistry and Purdue University Center of Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA

    Kavita Shah

  2. Department of Biochemistry, Purdue University, West Lafayette, IN, 47907, USA

    Sandra Rossie

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Correspondence to Kavita Shah.

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Shah, K., Rossie, S. Tale of the Good and the Bad Cdk5: Remodeling of the Actin Cytoskeleton in the Brain. Mol Neurobiol 55, 3426–3438 (2018). https://doi.org/10.1007/s12035-017-0525-3

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