Commitment of 1-methyl-4-phenylpyrinidinium Ion-Induced Neuronal Cell Death by Proteasome-Mediated Degradation of p35 Cyclin-Dependent Kinase 5 Activator

J Biol Chem. 2009 Sep 18;284(38):26029-39. doi: 10.1074/jbc.M109.026443. Epub 2009 Jul 28.

Abstract

The dysfunction of proteasomes and mitochondria has been implicated in the pathogenesis of Parkinson disease. However, the mechanism by which this dysfunction causes neuronal cell death is unknown. We studied the role of cyclin-dependent kinase 5 (Cdk5)-p35 in the neuronal cell death induced by 1-methyl-4-phenylpyrinidinium ion (MPP+), which has been used as an in vitro model of Parkinson disease. When cultured neurons were treated with 100 microM MPP+, p35 was degraded by proteasomes at 3 h, much earlier than the neurons underwent cell death at 12-24 h. The degradation of p35 was accompanied by the down-regulation of Cdk5 activity. We looked for the primary target of MPP+ that triggered the proteasome-mediated degradation of p35. MPP+ treatment for 3 h induced the fragmentation of the mitochondria, reduced complex I activity of the respiratory chain without affecting ATP levels, and impaired the mitochondrial import system. The dysfunction of the mitochondrial import system is suggested to up-regulate proteasome activity, leading to the ubiquitin-independent degradation of p35. The overexpression of p35 attenuated MPP+-induced neuronal cell death. In contrast, depletion of p35 with short hairpin RNA not only induced cell death but also sensitized to MPP+ treatment. These results indicate that a brief MPP+ treatment triggers the delayed neuronal cell death by the down-regulation of Cdk5 activity via mitochondrial dysfunction-induced up-regulation of proteasome activity. We propose a role for Cdk5-p35 as a survival factor in countering MPP+-induced neuronal cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / genetics
  • Adenosine Triphosphate / metabolism
  • Animals
  • Biological Transport / drug effects
  • Biological Transport / genetics
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Line
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / metabolism
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Electron Transport / drug effects
  • Electron Transport / genetics
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Humans
  • Mice
  • Mice, Inbred ICR
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Models, Biological*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Piperidines / pharmacology*
  • Proteasome Endopeptidase Complex / metabolism*
  • Rats
  • Time Factors

Substances

  • Nerve Tissue Proteins
  • Piperidines
  • neuronal Cdk5 activator (p25-p35)
  • Adenosine Triphosphate
  • Cyclin-Dependent Kinase 5
  • CDK5 protein, human
  • Cdk5 protein, mouse
  • Cdk5 protein, rat
  • Proteasome Endopeptidase Complex
  • Electron Transport Complex I