Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson's disease

Neuron. 2007 Jul 5;55(1):37-52. doi: 10.1016/j.neuron.2007.05.033.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / enzymology
  • Cerebral Cortex / metabolism
  • Cyclin-Dependent Kinase 5 / physiology*
  • Gene Transfer Techniques
  • Homeodomain Proteins / metabolism
  • Homeodomain Proteins / physiology*
  • Immunohistochemistry
  • Immunoprecipitation
  • MPTP Poisoning / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Neurons / enzymology
  • Neurons / metabolism
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / metabolism*
  • Phosphorylation
  • Reactive Oxygen Species / metabolism
  • Substantia Nigra / cytology
  • Substantia Nigra / enzymology


  • Homeodomain Proteins
  • Prrx2 protein, mouse
  • Reactive Oxygen Species
  • Cyclin-Dependent Kinase 5