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.
Camins
Antoni
A
Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia, Universitat de Barcelona, E-08028 Barcelona, Spain. camins@ub.edu
Verdaguer
Ester
E
Folch
Jaume
J
Canudas
Anna Maria
AM
Pallàs
Mercè
M
D000544:Alzheimer Disease / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013494:Supranuclear Palsy, Progressive / Q000378:metabolism
C108298:Cdk5 activator p39; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5