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Analysis of axonal degeneration mechanism by mitochondrial respiratory suppression in Parkinson's disease

Research Project

Project/Area Number 19K07369
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionOkayama University

Principal Investigator

Murata Hitoshi  岡山大学, 医歯薬学域, 講師 (90579096)

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)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
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)
KeywordsSARM1 / 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
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。

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.

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。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (16 results)

All 2021 2020 2019

All Journal Article (9 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 9 results,  Open Access: 9 results) Presentation (6 results) (of which Invited: 1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Neuroplastinβ-mediated upregulation of solute carrier family 22 member 18 antisense (SLC22A18AS) plays a crucial role in the epithelial-mesenchymal transition, leading to lung cancer cells' enhanced motility2020

    • Author(s)
      Bajkowska Karolina、Sumardika I. Wayan、Tomonobu Nahoko、Chen Youyi、Yamamoto Ken-ichi、Kinoshita Rie、Murata Hitoshi、Gede Yoni Komalasari Ni Luh、Jiang Fan、Yamauchi Akira、Winarsa Ruma I. Made、Kasano-Camones Carlos Ichiro、Inoue Yusuke、Sakaguchi Masakiyo
    • Journal Title

      Biochemistry and Biophysics Reports

      Volume: 22 Pages: 100768-100768

    • DOI

      10.1016/j.bbrep.2020.100768

    • NAID

      120006890008

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis2020

    • Author(s)
      Araki Kota、Kinoshita Rie、Tomonobu Nahoko、Gohara Yuma、Tomida Shuta、Takahashi Yuta、Senoo Satoru、Taniguchi Akihiko、Itano Junko、Yamamoto Ken-ichi、Murata Hitoshi、Suzawa Ken、Shien K、Yamamoto H、Okazaki M、Sugimoto S、Ichimura K、Nishibori M、Miyahara N、Toyooka S、Sakaguchi Masakiyo
    • Journal Title

      Journal of Molecular Medicine

      Volume: 99 Issue: 1 Pages: 131-145

    • DOI

      10.1007/s00109-020-02001-x

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Xylitol acts as an anticancer monosaccharide to induce selective cancer death via regulation of the glutathione level2020

    • Author(s)
      Tomonobu Nahoko、Komalasari Ni Luh Gede Yoni、Sumardika I Wayan、Jiang Fan、Chen Youyi、Yamamoto Ken-ichi、Kinoshita Rie、Murata Hitoshi、Inoue Yusuke、Sakaguchi Masakiyo
    • Journal Title

      Chemico-Biological Interactions

      Volume: 324 Pages: 109085-109085

    • DOI

      10.1016/j.cbi.2020.109085

    • NAID

      120006892917

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Convenient methodology for extraction and subsequent selective propagation of mouse melanocytes in culture from adult mouse skin tissue.2019

    • Author(s)
      Tomonobu N, Kinoshita R, Sumardika IW, Chen Y, Inoue Y, Yamauchi A, Yamamoto KI, Murata H, Sakaguchi M
    • Journal Title

      Biochem Biophys Rep.

      Volume: - Pages: 100619-100619

    • DOI

      10.1016/j.bbrep.2019.100619

    • NAID

      120006948964

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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
    • Journal Title

      Oncol Res

      Volume: - Issue: 6 Pages: 713-727

    • DOI

      10.3727/096504018x15433161908259

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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
    • Journal Title

      Mol Carcinog.

      Volume: - Issue: 6 Pages: 980-995

    • DOI

      10.1002/mc.22987

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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
    • Journal Title

      Cancer Lett.

      Volume: - Pages: 178-190

    • DOI

      10.1016/j.canlet.2019.03.023

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts2019

    • Author(s)
      Mitsui Yosuke、Tomonobu Nahoko、Watanabe Masami、Kinoshita Rie、Sumardika I Wayan、Youyi Chen、Murata Hitoshi et al.
    • Journal Title

      Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics

      Volume: 27 Issue: 8 Pages: 945-956

    • DOI

      10.3727/096504019x15555408784978

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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.
    • Journal Title

      Neoplasia.

      Volume: 21(7) Issue: 7 Pages: 627-640

    • DOI

      10.1016/j.neo.2019.04.006

    • NAID

      120006948963

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 疾患特異的iPS細胞と動物モデルを用いたパーキンソン病における軸索変性誘導分子SARM1のリン酸化制御解析2021

    • Author(s)
      村田等、越智俊樹、友信奈保子、山本健一、木下理恵、阪口政清
    • Organizer
      第93回日本組織培養学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 軸索変性誘導分子SARM1を標的とした化学療法誘発性末梢神経障害(CIPN)を抑制する低分子化合物2021

    • Author(s)
      村田等
    • Organizer
      第8回DSANJ Digital Bio Conference
    • Related Report
      2021 Annual Research Report
  • [Presentation] ロテノン誘発パーキンソニズムの病態形成におけるSARM1リン酸化制御の意義2020

    • Author(s)
      村田等、越智俊樹、山本健一、木下理恵、阪口政清
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 分泌性S100A11は膵臓癌の細胞運動性を高める腫瘍周囲の繊維芽細胞を活性化する2020

    • Author(s)
      合原勇馬、光井洋介、友信奈保子、木下理恵、山本健一、山内明、山村真弘、近藤英作、豊岡伸一、那須保友、村田等、阪口政清
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] Regulation of SARM1-NAD+ cleavage activity and mitochondrial function through phosphorylation by JNK2019

    • Author(s)
      村田等、山本健一、木下理恵、阪口政清
    • Organizer
      Neuro2019
    • Related Report
      2019 Research-status Report
  • [Presentation] JNKによるリン酸化を介したSARM1のNAD+代謝と軸索変性への寄与2019

    • Author(s)
      村田等、阪口政清
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Patent(Industrial Property Rights)] 化合物、神経系疾患の予防又は治療薬2021

    • Inventor(s)
      村田等、阪口政清、安藤 隆幸、福田 達也、中村 仁
    • Industrial Property Rights Holder
      村田等、阪口政清、安藤 隆幸、福田 達也、中村 仁
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-135934
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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