Elucidation of the regulatory mechanism of the axon degeneration-inducing molecule SARM1 and development of SARM1 inhibitors

• Project/Area Number: 22K06884
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Okayama 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)
• Project Period (FY): 2022-04-01 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2024: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: SARM1 / NAD / 軸索変性 / ミトコンドリア / パーキンソン病

Outline of Research at the Start

本研究では補酵素NAD+の分解を介して軸索変性を誘導する分子SARM1に着目し、軸索変性が病態進行に関与すると考えられているパーキンソン病の治療応用に向けた研究を行う。我々は独自のスクリーニングからSARM1のNAD+分解活性を阻害する化合物とSARM1の分解制御に関わる新知見を得ているので、そのメカニズム解明に取り組み、軸索変性を標的としたSARM1阻害薬の実用化に向けた研究を進める。

Outline of Final Research Achievements

We conducted research to elucidate the regulation mechanism of the NAD consuming enzyme SARM1, which is involved in axonal degeneration and neuronal cell death, and to improve the pathology of nervous system diseases such as Parkinson's disease (PD) by using a uniquely discovered SARM1 inhibitor compound.
We found that the STAT1/3 pathway is involved in the regulation mechanism that suppresses the NAD-cleavage activity of SARM1. STAT1/3 inhibited JNK-mediated phosphorylation of SARM1 and suppressed the decrease in NAD levels. We demonstrated that activation of SARM1 is involved in the pathogenesis of PD using neurons derived from a PD patient and a PD model mouse. When a SARM1 inhibitor compound was administered to a peripheral neuropathy model mouse, it was confirmed that axonal degeneration was suppressed and the pathology was improved.

Academic Significance and Societal Importance of the Research Achievements

我々はNAD分解酵素SARM1のリン酸化による制御メカニズムの解明を行い、リン酸化SARM1のNAD分解活性を阻害する低分子化合物を見出した。この化合物はSARM1阻害を通じて、軸索変性や細胞死を抑制し、末梢神経障害の病態を改善した。今後、化合物の構造最適化研究等を進めることによって、パーキンソン病等の神経系疾患の病態改善に向けたSARM1阻害薬の開発につながることが期待される。

Research Products

• [Journal Article] An S100A8/A9 neutralizing antibody potently aameliorates contact hypersensitivity and apoptotic dermatitis symptoms (2025)
  • Author(s): Gohara Y, Kinoshita R, Tomonobu N, ..., Sakaguchi Y, Futami J, Inoue Y, Kondo E, Toyooka S, Morizane S, Ishiko A, Morita S, Sagayama K, Nakao K, Sakaguchi M
  • Journal Title: J Invest Dermatol. Volume: S0022-202X(25)00029-6 Issue: 8 Pages: 00029-6
  • DOI: 10.1016/j.jid.2025.01.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced design of pCMViR-TSC plasmid vector for sustainably high cargo gene expression in mammalian cells (2024)
  • Author(s): Sakaguchi M, Kinoshita R, Tomonobu N, Sakaguchi Y, Futami J, Yamauchi A, Murata H, Yamamoto KI, ..., Sagayama K, Toyooka S, Kondo E, Inoue Y
  • Journal Title: In Vitro Cell Dev Biol Anim. Volume: 60 Issue: 10 Pages: 1215-1227
  • DOI: 10.1007/s11626-024-00992-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] S100A11 is involved in the progression of colorectal cancer through the desmosome-catenin-TCF signaling pathway (2024)
  • Author(s): Zhou Jin、Murata Hitoshi、Tomonobu Nahoko、Mizuta Naoko、Yamakawa Atsuko、Yamamoto Ken-ichi、Kinoshita Rie、Sakaguchi Masakiyo
  • Journal Title: In Vitro Cellular & Developmental Biology - Animal Volume: 60 Issue: 10 Pages: 1138-1149
  • DOI: 10.1007/s11626-024-00930-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lysyl oxidase-like 4 promotes the invasiveness of triple-negative breast cancer cells by orchestrating the invasive machinery formed by annexin A2 and S100A11 on the cell surface (2024)
  • Author(s): Takahashi Tetta、Tomonobu Nahoko、Kinoshita Rie、Yamamoto Ken-ichi、Murata Hitoshi、Komalasari Ni Luh Gede Yoni、...、Honjo Tomoko、Sakaguchi Yoshihiko、Yamauchi Akira、Kuribayashi Futoshi、Kondo Eisaku、Inoue Yusuke、Futami Junichiro、Toyooka Shinichi、Zamami Yoshito、Sakaguchi Masakiyo
  • Journal Title: Frontiers in Oncology Volume: 14 Pages: 1371342-1371342
  • DOI: 10.3389/fonc.2024.1371342
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dissection of the signal transduction machinery responsible for the lysyl oxidase-like 4-mediated increase in invasive motility in triple-negative breast cancer cells: mechanistic insight into the integrin-β1-NF-κB-MMP9 axis (2024)
  • Author(s): Fan Jiang, Youyi Chen, Nahoko Tomonobu, Rie Kinoshita, ..., Junichiro Futami, Eisaku Kondo , Yusuke Inoue, Shinichi Toyooka, Masakiyo Sakaguchi
  • Journal Title: Frontiers in Oncology Volume: 14 Pages: 1371307-1371307
  • DOI: 10.3389/fonc.2024.1371307
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] STAT1/3 signaling suppresses axon degeneration and neuronal cell death through regulation of NAD+-biosynthetic and consuming enzymes. (2023)
  • Author(s): Murata H, Yasui Y, Oiso K, Ochi T, Tomonobu N, Yamamoto KI, Kinoshita R, Sakaguchi M
  • Journal Title: Cellular Signalling Volume: 108 Pages: 110717-110717
  • Peer Reviewed / Open Access
• [Journal Article] Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells. (2023)
  • Author(s): Yuma Gohara, Nahoko Tomonobu, Rie Kinoshita, Junichiro Futami, Lena Audebert, Youyi Chen, Ni Luh Gede Yoni Komalasari, Fan Jiang, Chikako Yoshizawa, Hitoshi Murata, Ken-Ichi Yamamoto, Masami Watanabe, Hiromi Kumon, Masakiyo Sakaguchi
  • Journal Title: Journal of molecular medicine (Berlin, Germany) Volume: 101 Issue: 4 Pages: 431-447
  • DOI: 10.1007/s00109-023-02292-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LOXL1 and LOXL4 are novel target genes of the Zn2+-bound form of ZEB1 and play a crucial role in the acceleration of invasive events in triple-negative breast cancer cells (2023)
  • Author(s): Daisuke Hirabayashi, Ken-ichi Yamamoto, Akihiro Maruyama, Nahoko Tomonobu, Rie Kinoshita, Youyi Chen, Ni Luh Gede Yoni Komalasari, Hitoshi Murata, Yuma Gohara, Fan Jiang, Jin Zhou, I Made Winarsa Ruma, I Wayan Sumardika, Akira Yamauchi, Futoshi Kuribayashi, Shinichi Toyooka, Yusuke Inoue, Masakiyo Sakaguchi
  • Journal Title: Frontiers in Oncology Volume: 13 Pages: 1142886-1142886
  • DOI: 10.3389/fonc.2023.1142886
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lysyl oxidase-like 4 exerts an atypical role in breast cancer progression that is dependent on the enzymatic activity that targets the cell-surface annexin A2 (2023)
  • Author(s): Sakaguchi, M., Komalasari, N. L. G. Y., Tomonobu, N., Kinoshita, R., Chen, Y., Sakaguchi, Y., Gohara, Y., Jiang, F., Yamamoto, K., Murata, H., Ruma, I. M. W., Sumardika, I. W., Zhou, J., Yamauchi, A., Kuribayashi, F., Inoue, Y., Toyooka, S.
  • Journal Title: Front. Oncol. Volume: 13 Pages: 1142907-1142907
  • DOI: 10.3389/fonc.2023.1142907
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphorylated SARM1 is involved in the pathological process of rotenone-induced neurodegeneration (2023)
  • Author(s): Murata Hitoshi、Phoo May Tha Zin、Ochi Toshiki、Tomonobu Nahoko、Yamamoto Ken-ichi、Kinoshita Rie、Miyazaki Ikuko、Nishibori Masahiro、Asanuma Masato、Sakaguchi Masakiyo
  • Journal Title: The Journal of Biochemistry Volume: 174 Issue: 6 Pages: 533-548
  • DOI: 10.1093/jb/mvad068
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Suppression of axon degeneration and cell death by STAT1/3 signaling through regulation of NAD+-biosynthetic and consuming enzymes (2024)
  • Author(s): Hitoshi Murata, Yu Yasui, Toshiki Ochi, Nahoko Tomonobu, Ken-ichi Yamamoto, Rie Kinoshita, Masakiyo Sakaguchi
  • Organizer: Neuro2024
• [Presentation] ヒトiPS細胞由来神経細胞と動物モデルを用いた軸索変性誘導分子SARM1の阻害剤開発 (2023)
  • Author(s): 村田 等, 安藤 隆幸, 安井 優, 越智 俊樹, 友信 奈保子, 山本 健一, 木下 理恵, 阪口 政清
  • Organizer: 日本組織培養学会 第95回大会
• [Presentation] STAT1/3シグナル経路によるNAD+代謝酵素制御を介した神経軸索変性と細胞死の抑制 (2023)
  • Author(s): 安井 優, 村田 等, 大磯 和真, 越智 俊樹, 友信 奈保子, 山本 健一, 木下 理恵, 阪口 政清
  • Organizer: 日本組織培養学会 第95回大会
• [Presentation] Suppression of axon degeneration and neuronal cell death by STAT1/3 signaling through regulation of NAD+-biosynthetic and consuming enzyme (2023)
  • Author(s): 村田 等, 安井 優, 越智 俊樹, 友信 奈保子, 山本 健一, 木下 理恵, 阪口 政清
  • Organizer: 第46回日本分子生物学会年会
• [Presentation] 軸索変性誘導分子 SARM1の阻害剤開発 (2022)
  • Author(s): 村田 等、安藤 隆幸、大磯 和真、友信 奈保子、山本 健一、木下 理恵、阪口 政清
  • Organizer: NEURO2022
• [Presentation] 神経軸索変性メカニズムの解明と創薬への応用 (2022)
  • Author(s): 村田 等
  • Organizer: 創薬・薬理フォーラム岡山
  • Invited