The role of CDK5/P25 formation/inhibition in neurodegeneration.

Cdk5 is an atypical cyclin-dependent kinase localized in the brain, and its activity is dependent upon binding to p35/p39. In addition, while cdk5 has important physiological functions related to brain development, the breakdown of cdk5/p35 into cdk5/p25 increases its kinase activity and neurotoxicity. Interestingly, in recent years increased cdk5/p25 expression has been demonstrated in the brains of patients with Alzheimer's and Parkinson's diseases. Experimental studies performed in neuronal cell cultures indicate that cdk5/p25 plays a prominent role in apoptosis. Moreover, an apoptotic pathway, via an intracellular calcium increase following calpain activation and cdk5/p25 formation, has been postulated. Cdk5/p25 subsequently phosphorylates the nuclear transcription factor myocyte enhancer factor (MEF2), thereby inhibiting its prosurvival activity. However, cdk5/p25 could phosphorylate other substrates such as tau and p53, as well as the retinoblastoma protein pRb. All these data lend credence to the hypothesis that cdk5/p25 acts as a master regulator of neuronal cell death. In addition, cdk5/p25 might also interact with other pathways such as glycogen synthetase kinase 3beta (GSK3beta) and c-JUN kinase. Drugs like roscovitine, flavopiridol, calpain inhibitors, kenpaullone and induribins, which inhibit cdk5/p25 formation, constitute potential drugs for the treatment of neurological disorders. Furthermore, the dual inhibitory effect of some of these drugs on cdk5 and GSK3beta could be beneficial.
AuthorsAntoni Camins, Ester Verdaguer, Jaume Folch, Anna Maria Canudas, Mercè Pallàs
JournalDrug news & perspectives (Drug News Perspect) Vol. 19 Issue 8 Pg. 453-60 (Oct 2006) ISSN: 0214-0934 [Print] Spain
PMID17160145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
Copyright(c) 2006 Prous Science. All rights reserved.
Chemical References
  • Cdk5 activator p39
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Protein Kinase Inhibitors
  • neuronal Cdk5 activator (p25-p35)
  • Cyclin-Dependent Kinase 5
  • Alzheimer Disease (metabolism)
  • Amyotrophic Lateral Sclerosis (metabolism)
  • Animals
  • Apoptosis (drug effects)
  • Cyclin-Dependent Kinase 5 (antagonists & inhibitors, metabolism)
  • Humans
  • Huntington Disease (metabolism)
  • Nerve Tissue Proteins (metabolism)
  • Neurodegenerative Diseases (metabolism, physiopathology)
  • Neurons (drug effects, metabolism)
  • Neuroprotective Agents (pharmacology)
  • Niemann-Pick Disease, Type C (metabolism)
  • Parkinson Disease (metabolism)
  • Protein Kinase Inhibitors (pharmacology)
  • Supranuclear Palsy, Progressive (metabolism)

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