title: Neuroprotective Mechanisms Mediated by CDK5 Inhibition.
abstract: Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase belonging to the family of cyclin-dependent kinases. In addition to maintaining the neuronal architecture, CDK5 plays an important role in the regulation of synaptic plasticity, neurotransmitter release, neuron migration and neurite outgrowth. Although various reports have shown links between neurodegeneration and deregulation of cyclin-dependent kinases, the specific role of CDK5 inhibition in causing neuroprotection in cases of neuronal insult or in neurodegenerative diseases is not wellunderstood. This article discusses current evidence for the involvement of CDK5 deregulation in neurodegenerative disorders and neurodegeneration associated with stroke through various mechanisms. These include upregulation of cyclin D1 and overactivation of CDK5 mediated neuronal cell death pathways, aberrant hyperphosphorylation of human tau proteins and/or neurofilament proteins, formation of neurofibrillary lesions, excitotoxicity, cytoskeletal disruption, motor neuron death (due to abnormally high levels of CDK5/p25) and colchicine- induced apoptosis in cerebellar granule neurons. A better understanding of the role of CDK5 inhibition in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious pharmacological inhibitors of CDK5 for therapeutic use against human neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis and neuronal loss associated with stroke.
authors.affiliation: Department of Biochemistry, College of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia. gmushtaq2001@gmail.com.
authors.forename: Gohar
authors.initials: G
authors.lastname: Mushtaq
authors.affiliation: Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National, Institute on Aging, National Institutes of Health, Biomedical Research Center, 251 Bayview Boulevard, Baltimore, MD 21224, USA. greign@grc.nia.nih.gov.
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Firoz
authors.initials: F
authors.lastname: Anwar
authors.forename: Fahad A
authors.initials: FA
authors.lastname: Al-Abbasi
authors.forename: Mazin A
authors.initials: MA
authors.lastname: Zamzami
authors.forename: Hasan A
authors.initials: HA
authors.lastname: Al-Talhi
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Kamal
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D051360:Cyclin-Dependent Kinase 5