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

Abstract

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.

• Authors: Antoni Camins, Ester Verdaguer, Jaume Folch, Anna Maria Canudas, Mercè Pallàs
• Journal: Drug news & perspectives (Drug News Perspect) Vol. 19 Issue 8 Pg. 453-60 (Oct 2006) ISSN: 0214-0934 [Print] United States
• PMID: 17160145 (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

Topics

• 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)