内在性ドパミンとプロテアソーム活性によるドパミンニューロン死の制御機構

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  • 泉 安彦
    京都大学大学院薬学研究科薬品作用解析学分野
  • 久米 利明
    京都大学大学院薬学研究科薬品作用解析学分野
  • 赤池 昭紀
    京都大学大学院薬学研究科薬品作用解析学分野

書誌事項

タイトル別名
  • Regulation of Dopaminergic Neuronal Death by Endogenous Dopamine and Proteasome Activity
  • ナイザイセイ ドパミン ト プロテアソーム カッセイ ニ ヨル ドパミンニューロンシ ノ セイギョ キコウ

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説明

  Parkinson disease is one of the most common neurodegenerative disorders and is characterized by the selective loss of dopaminergic neurons in the substantia nigra. Although endogenous dopamine itself could serve as a vulnerability factor for dopaminergic neurons, the mechanism by which dopamine contributes to dopaminergic neuronal death remains unknown. In addition, although a decrease in proteasome activity was found in patients with sporadic Parkinson disease, the relationship between the ubiquitin-proteasome system and dopaminergic neuronal death remains to be elucidated. Here we provide an overview of the roles of endogenous dopamine and proteasome activity in dopaminergic cell death. Treatment of catecholaminergic PC12 cells with the herbicide paraquat, a potential risk factor for the development of Parkinson disease, induced an increase in dopamine content, and depletion of intracellular dopamine suppressed paraquat-induced cytotoxicity. Although glutathione, which scavenged dopamine oxidation intermediate, provided almost complete protection against dopamine-mediated toxicity, catalase provided only partial protection against cell death caused by dopamine. These data suggest that the generation of dopamine oxidation intermediate, rather than that of reactive oxygen species, plays a pivotal role in dopamine-induced toxicity. Moreover, treatment with paraquat induced a decrease in proteasome activity, and proteasome inhibition suppressed dopamine-mediated cytotoxicity. Suppression of proteasome activity stimulated the NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway, and elevated γ-glutamylcysteine synthetase mRNA and glutathione content. Furthermore, suppression of the paraquat-induced increase in gluthathione content exacerbated paraquat toxicity. These results suggest that the reduction of proteasome activity may be involved in cellular defense mechanisms against dopamine-mediated paraquat toxicity.<br>

収録刊行物

  • 薬学雑誌

    薬学雑誌 131 (1), 21-27, 2011-01-01

    公益社団法人 日本薬学会

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