title: 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.affiliation: Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia, Universitat de Barcelona, E-08028 Barcelona, Spain. camins@ub.edu
authors.forename: Antoni
authors.initials: A
authors.lastname: Camins
authors.forename: Ester
authors.initials: E
authors.lastname: Verdaguer
authors.forename: Jaume
authors.initials: J
authors.lastname: Folch
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Canudas
authors.forename: Mercè
authors.initials: M
authors.lastname: Pallàs
mesh_terms: 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
chemical_list: 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