A Tale of the Good and Bad: Remodeling of the Microtubule Network in the Brain by Cdk5

Abstract

Cdk5, a cyclin dependent kinase family member, is a global orchestrator of neuronal cytoskeletal dynamics. During embryogenesis, Cdk5 is indispensable for brain development. In adults, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation, drug addiction, pain signaling and long term behavior changes through long term potentiation and long term depression, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity becomes deregulated in various brain disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, attention-deficit hyperactivity disorder, epilepsy, schizophrenia and ischemic stroke; these all result in profound remodeling of the neuronal cytoskeleton. This Commentary specifically focuses on the pleiotropic contribution of Cdk5 in regulating neuronal microtubule remodeling. Because the vast majority of the physiological substrates of Cdk5 are associated with the neuronal cytoskeleton, our emphasis is on the Cdk5 substrates, such as CRMP2, stathmin, drebrin, dixdc1, axin, GKAP, kinesin-5, tau and PSD-95, that have allowed to unravel the molecular mechanisms through which Cdk5 exerts its divergent roles in regulating neuronal microtubule dynamics, both in healthy and disease states.

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…Cdk5 is a member of the cyclindependent kinase family, which has been implicated in drug addiction, pain signaling, microtubule dynamics, and learning and memory formation (95,96). Cdk5 is abundant in neuronal cells and is activated by complexing with p35 or p39 protein.…”

Late phase cell cycle proteins in Alzheimer’s disease: a possible target for therapy?

“…It is well known that cdk 5 dysregulation may cause neuroinflammation and neurodegeneration [51] One study demonstrated that in response to Aβ, neurons will reenter the cell cycle and transit through the cell cycle until the M phase, and that these processes are mediated by CDK 5 and its downstream effectors. So, the importance of CDK 5 as a neuronal ''switch'' is due to the fact that aberrant hyperactivation of CDK 5 by the production of truncated activator p25 results in the formation of hyperphosphorylated TAU, neuroinflamation, amyloid deposition and neuronal death in vivo and in vitro [52].…”

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

“…Cyclin-dependent kinase-5 (Cdk5) shares high homology with other family members; however, it differs from them by adopting unique activation strategies and distinctive cellular functions [3–5]. Cdk5 is not activated by classical cyclins such as cyclin A, cyclin D, and cyclin E but binds to its own specific protein partners, p35, p39, and cyclin I [6–8].…”