title: Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity.
abstract: Cyclin dependent kinase-5 (Cdk5) activity is deregulated in Alzheimer's disease (AD) and contributes to all three hallmarks: neurotoxic β-amyloid formation, neurofibrillary tangles, and neuronal death. However, the mechanism leading to Cdk5 deregulation remains controversial. Cdk5 deregulation in AD is usually linked to the formation of p25, a proteolysis product of Cdk5 activator p35, which leads to Cdk5 mislocalization and hyperactivation. A few studies have indeed shown increased p25 levels in AD brains; however, others have refuted this observation. These contradictory findings suggest that additional factors contribute to Cdk5 deregulation. This study identified glutathione-S-transferase pi 1 (GSTP1) as a novel Cdk5 regulatory protein. We demonstrate that it is a critical determinant of Cdk5 activity in human AD brains and various cancer and neuronal cells. Increased GSTP1 levels were consistently associated with reduced Cdk5 activity. GSTP1 directly inhibits Cdk5 by dislodging p25/p35, and indirectly by eliminating oxidative stress. Cdk5 promotes and is activated by oxidative stress, thereby engaging a feedback loop which ultimately leads to cell death. Not surprisingly, GSTP1 transduction conferred a high degree of neuroprotection under neurotoxic conditions. Given the critical role of oxidative stress in AD pathogenesis, an increase in GSTP1 level may be an alternative way to modulate Cdk5 signaling, eliminate oxidative stress, and prevent neurodegeneration.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Kai-Hui
authors.initials: KH
authors.lastname: Sun
authors.forename: Kuei-Hua
authors.initials: KH
authors.lastname: Chang
authors.forename: Sara
authors.initials: S
authors.lastname: Clawson
authors.forename: Soumitra
authors.initials: S
authors.lastname: Ghosh
authors.forename: Hamid
authors.initials: H
authors.lastname: Mirzaei
authors.forename: Fred
authors.initials: F
authors.lastname: Regnier
authors.forename: Kavita
authors.initials: K
authors.lastname: Shah
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology; D000818:Animals; D001921:Brain / Q000201:enzymology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051549:Glutathione S-Transferase pi / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D009195:Peroxidase / Q000378:metabolism; D011180:Postmortem Changes; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D009195:Peroxidase; D051549:Glutathione S-Transferase pi; D051360:Cyclin-Dependent Kinase 5