title: Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson's disease.
abstract: We reported previously that calpain-mediated Cdk5 activation is critical for mitochondrial toxin-induced dopaminergic death. Here, we report a target that mediates this loss. Prx2, an antioxidant enzyme, binds Cdk5/p35. Prx2 is phosphorylated at T89 in neurons treated with MPP+ and/or MPTP in animals in a calpain/Cdk5/p35-dependent manner. This phosphorylation reduces Prx2 peroxidase activity. Consistent with this, p35-/- neurons show reduced oxidative stress upon MPP+ treatment. Expression of Prx2 and Prx2T89A, but not the phosphorylation mimic Prx2T89E, protects cultured and adult neurons following mitochondrial insult. Finally, downregulation of Prx2 increases oxidative stress and sensitivity to MPP+. We propose a mechanistic model by which mitochondrial toxin leads to calpain-mediated Cdk5 activation, reduced Prx2 activity, and decreased capacity to eliminate ROS. Importantly, increased Prx2 phosphorylation also occurs in nigral neurons from postmortem tissue from Parkinson's disease patients when compared to control, suggesting the relevance of this pathway in the human condition.
authors.affiliation: Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, K1H 8M5 ON, Canada.
authors.forename: Dianbo
authors.initials: D
authors.lastname: Qu
authors.forename: Juliet
authors.initials: J
authors.lastname: Rashidian
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Mount
authors.forename: Hossein
authors.initials: H
authors.lastname: Aleyasin
authors.forename: Mohammad
authors.initials: M
authors.lastname: Parsanejad
authors.forename: Arman
authors.initials: A
authors.lastname: Lira
authors.forename: Emdadul
authors.initials: E
authors.lastname: Haque
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Steve
authors.initials: S
authors.lastname: Callaghan
authors.forename: Mireille
authors.initials: M
authors.lastname: Daigle
authors.forename: Maxime W C
authors.initials: MW
authors.lastname: Rousseaux
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.forename: Paul R
authors.initials: PR
authors.lastname: Albert
authors.forename: Inez
authors.initials: I
authors.lastname: Vincent
authors.forename: John M
authors.initials: JM
authors.lastname: Woulfe
authors.forename: David S
authors.initials: DS
authors.lastname: Park
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D018014:Gene Transfer Techniques; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013378:Substantia Nigra / Q000166:cytology / Q000201:enzymology
chemical_list: D018398:Homeodomain Proteins; C115469:Prrx2 protein, mouse; D017382:Reactive Oxygen Species; D051360:Cyclin-Dependent Kinase 5