Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson's disease.
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.
Qu
Dianbo
D
Ottawa Health Research Institute, Neuroscience Group, University of Ottawa, Ottawa, K1H 8M5 ON, Canada.
Rashidian
Juliet
J
Mount
Matthew P
MP
Aleyasin
Hossein
H
Parsanejad
Mohammad
M
Lira
Arman
A
Haque
Emdadul
E
Zhang
Yi
Y
Callaghan
Steve
S
Daigle
Mireille
M
Rousseaux
Maxime W C
MW
Slack
Ruth S
RS
Albert
Paul R
PR
Vincent
Inez
I
Woulfe
John M
JM
Park
David S
DS
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
D018398:Homeodomain Proteins; C115469:Prrx2 protein, mouse; D017382:Reactive Oxygen Species; D051360:Cyclin-Dependent Kinase 5