Commitment of 1-methyl-4-phenylpyrinidinium ion-induced neuronal cell deathby proteasome-mediated degradation of p35 cyclin-dependent kinase 5 activator

Ryo Endo, Taro Saito, Akiko Asada, Hiroyuki Kawahara, Toshio Ohshima, Shin Ichi Hisanaga

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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 μM 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.

Original languageEnglish
Pages (from-to)26029-26039
Number of pages11
JournalJournal of Biological Chemistry
Volume284
Issue number38
DOIs
Publication statusPublished - 2009 Sep 18

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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