| Project/Area Number |
17K08531
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
General physiology
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| Research Institution | University of Toyama |
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Principal Investigator |
Fujii Takuto 富山大学, 学術研究部薬学・和漢系, 助教 (50567980)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | カチオン輸送ポンプ / ATP13A2 / パーキンソン病 / リソソーム / 神経細胞 / 生理学 / 蛋白質 / 薬学 / 神経科学 |
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| Outline of Final Research Achievements |
Parkinson’s disease (PD) is one of the most common movement disorders. Dysfunction of ATP13A2, a lysosomal orphan P-type ATPase, diminishes lysosomal acidification and degradation, and induces mitochondrial dysregulation in PD pathogenesis. Therefore, ATP13A2 has potential as a therapeutic target for PD, however, conclusive evidence for cation substrates of ATP13A2 has not yet been provided. In this study, we found that ATPase activity of ATP13A2 was increased in a K+ concentration-dependent manner at acidic pH. ATP-dependent 86Rb+ (K+ analog) efflux from lysosomes was significantly increased in ATP13A2-expressing cells. Interestingly, PD-associated mutations strongly reduced the ATPase activity and 86Rb+ efflux of ATP13A2. These results suggest that ATP13A2 functions as an acidic-activated K+ pump in lysosomes, and dysfunction of K+ efflux by ATP13A2 may be implicated in PD.
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| Academic Significance and Societal Importance of the Research Achievements |
神経細胞のリソソームに発現するPD病因遺伝子のATP13A2がK+排出ポンプとして機能し、その輸送機能異常がPD病態に関連することを見出した。これは、「カチオンポンプの機能異常が引き起こすPD発症機構」という新たな概念であり、従来のドパミン補充療法とは異なるPD治療の新しい創薬基盤の構築につながる成果である。従って、本研究の学術的意義、臨床的意義および社会的貢献度は大きいと考えられる。さらに、ATP13A2はリソソームの機能維持に重要な役割を担っていることから、難治性疾患克服研究事業の対象疾患に指定されている種々のリソソーム病発症機構の解明および創薬展開など他分野への波及効果も期待できる。
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