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

    Research output: Contribution to journalArticle

    24 Citations (Scopus)

    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

    Fingerprint

    Cyclin-Dependent Kinase 5
    Cell death
    Proteasome Endopeptidase Complex
    Cell Death
    Ions
    Degradation
    Mitochondria
    Neurons
    Parkinson Disease
    Up-Regulation
    Down-Regulation
    Electron Transport
    Ubiquitin
    Small Interfering RNA
    Adenosine Triphosphate

    ASJC Scopus subject areas

    • Biochemistry
    • Cell Biology
    • Molecular Biology
    • Medicine(all)

    Cite this

    Commitment of 1-methyl-4-phenylpyrinidinium ion-induced neuronal cell deathby proteasome-mediated degradation of p35 cyclin-dependent kinase 5 activator. / Endo, Ryo; Saito, Taro; Asada, Akiko; Kawahara, Hiroyuki; Ohshima, Toshio; Hisanaga, Shin Ichi.

    In: Journal of Biological Chemistry, Vol. 284, No. 38, 18.09.2009, p. 26029-26039.

    Research output: Contribution to journalArticle

    Endo, Ryo ; Saito, Taro ; Asada, Akiko ; Kawahara, Hiroyuki ; Ohshima, Toshio ; Hisanaga, Shin Ichi. / Commitment of 1-methyl-4-phenylpyrinidinium ion-induced neuronal cell deathby proteasome-mediated degradation of p35 cyclin-dependent kinase 5 activator. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 38. pp. 26029-26039.
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