Analysis of axonal degeneration mechanism by mitochondrial respiratory suppression in Parkinson's disease
| Project/Area Number |
19K07369
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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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| Review Section |
Basic Section 48040:Medical biochemistry-related
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| Research Institution | Okayama University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
阪口 政清 岡山大学, 医歯薬学域, 教授 (70379840)
浅沼 幹人 岡山大学, 医歯薬学域, 教授 (00273970)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | SARM1 / ミトコンドリア / 軸索変性 / パーキンソン病 / リン酸化 / ミトコンドリア呼吸 |
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| Outline of Research at the Start |
申請者はミトコンドリアに局在するSARM1がミトコンドリア呼吸を阻害し、神経細胞の軸索変性に関与することを示唆する解析結果を得た。本研究ではSARM1やその結合タンパク質の機能解析を行い、SARM1を介したミトコンドリア呼吸阻害がいかにして軸索変性を誘導するのかを解明する。
またパーキンソン病患者由来の神経細胞を用いた解析で、SARM1の異常活性化や軸索変性誘導を確認しているので、SARM1を標的とすることによってパーキンソン病の病態改善が可能かどうかを検証する。
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| Outline of Final Research Achievements |
We analyzed the mechanism of axonal degeneration induction by mitochondrial respiratory inhibition mediated by abnormal activation of SARM1. SARM1 was activated by JNK-mediated phosphorylation and inhibited mitochondrial respiration by hydrolyzing NAD+. In order to see the effect of this pathway on the pathogenesis of Parkinson's disease (PD), we performed analysis using neurons derived from PD patients lacking the Parkin gene and rotenone that induces PD-like symptoms. Parkin deletion and exposure to rotenone increased SARM1 phosphorylation levels and increased the rate of axonal degeneration and cell death. Similar phenomena were observed in vivo, suggesting that abnormal activation of SARM1 is involved in the pathogenesis of PD.
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| Academic Significance and Societal Importance of the Research Achievements |
パーキンソン病は中脳黒質から線条体に軸索を投射するドーパミン作動性神経の脱落を主な原因とする神経変性疾患である。我々はミトコンドリア呼吸を阻害し、軸索変性を誘導する分子であるSARM1の解析を行い、リン酸化によるSARM1の異常活性化がパーキンソン病の病態進行に関与する可能性を示す解析結果を得た。リン酸化SARM1の機能を阻害する低分子化合物を見出したので、今後パーキンソン病の治療薬開発に繋がるように研究を更に進めていく。
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Report
(4 results)
Research Products
(16 results)
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[Journal Article] Extracellular S100A11 plays a critical role in spread of the fibroblast population in pancreatic cancers2019
Author(s)
Takamatsu H, Yamamoto K, Tomonobu N, Murata H, Inoue Y, Yamauchi A, Sumardika W, Youyi C, Kinoshita R, Yamamura M, Fujiwara H, Mitsui Y, Araki K, Futami J, Saito K, Iioka H, Ruma MW, Putranto EW, Nishibori M, Kondo E, Yamamoto Y, Toyooka S, Sakaguchi M
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Journal Title
Oncol Res
Volume: -
Issue: 6
Pages: 713-727
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Neuroplastin-β mediates S100A8/A9-induced lung cancer disseminative progression.2019
Author(s)
Sumardika IW, Chen Y, Tomonobu N, Kinoshita R, Ruma IMW, Sato H, Kondo E, Inoue Y, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Putranto EW, Hibino T, Nishibori M, Toyooka S, Sakaguchi M
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Journal Title
Mol Carcinog.
Volume: -
Issue: 6
Pages: 980-995
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion.2019
Author(s)
Chen Y, Sumardika IW, Tomonobu N, Winarsa Ruma IM, Kinoshita R, Kondo E, Inoue Y, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Liu M, Futami J, Sasai K, Katayama H, Kubo M, Putranto EW, Hibino T, Sun B, Nishibori M, Toyooka S, Sakaguchi M
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Journal Title
Cancer Lett.
Volume: -
Pages: 178-190
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness.2019
Author(s)
Chen Y, Sumardika IW, Tomonobu N, Kinoshita R, Inoue Y, Iioka H, Mitsui Y, Saito K, Ruma IMW, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Kubo M, Putranto EW, Murakami T, Liu M, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M.
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Journal Title
Neoplasia.
Volume: 21(7)
Issue: 7
Pages: 627-640
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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