The role of CDK5/P25 formation/inhibition in neurodegeneration

Drug News Perspect. 2006 Oct;19(8):453-60. doi: 10.1358/dnp.2006.19.8.1043961.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Apoptosis* / drug effects
  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 5 / metabolism*
  • Humans
  • Huntington Disease / metabolism
  • Nerve Tissue Proteins / metabolism*
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / physiopathology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neuroprotective Agents / pharmacology
  • Niemann-Pick Disease, Type C / metabolism
  • Parkinson Disease / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Supranuclear Palsy, Progressive / metabolism


  • Cdk5 activator p39
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Protein Kinase Inhibitors
  • neuronal Cdk5 activator (p25-p35)
  • Cyclin-Dependent Kinase 5