Analysis of mitochondrial respiratoty regulation mechanism and its failure in neurodegenerative disease

• Project/Area Number: 16K19037
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Okayama University
• Principal Investigator: Murata Hitoshi 岡山大学, 医歯薬学総合研究科, 講師 (90579096)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: ミトコンドリア / SARM1 / JNK / パーキンソン病 / NAD / リン酸化 / 細胞・組織 / 脳神経疾患

Outline of Final Research Achievements

We analyzed regulation mechanism of SARM1 involved in mitochondrial respiratory regulation. SARM1 is phosphorylated by rotenone or praquat which induces Parkinson’s disease-like symptoms. The kinase is JNK and the phosphorylation site of SARM1 is Ser548. SARM1 has an enzymatic activity to degrade NAD, and activation of SARM1 suppressed mitochondrial ATP production through degradation of NAD. The NAD degradation activity of SARM1 was attenuated by Ala mutation of Ser548. Phosphorylation levels of SARM1 in Parkinson’s disease patient derived neurons were higher than in healthy donor derived neurons, suggesting that SARM1 activation may be involved in disease progression.

Academic Significance and Societal Importance of the Research Achievements

我々はパーキンソン病をはじめとする神経変性疾患の病態形成メカニズムを解明し、疾患の発症や進行を抑えることができる薬剤開発を目指して研究を行っている。今回我々はミトコンドリア呼吸を阻害し、神経軸索変性に関与するSARM1の研究を行い、新規にJNKを介したリン酸化制御機構を見出した。パーキンソン病患者由来の神経細胞ではSARM1のリン酸化が上昇しており、パーキンソン病の病態形成にSARM1の活性化が関与している可能性を見出した点に学術的・社会的意義がある。

Research Products

• [Journal Article] c-Jun N-terminal kinase (JNK)-mediated phosphorylation of SARM1 regulates NAD(+) cleavage activity to inhibit mitochondrial respiration. (2018)
  • Author(s): Murata H, Khine CC, Nishikawa A, Yamamoto KI, Kinoshita R, Sakaguchi M.
  • Journal Title: J Biol Chem. Volume: 293 Issue: 49 Pages: 18933-18943
  • DOI: 10.1074/jbc.ra118.004578
  • Peer Reviewed
• [Journal Article] exSSSRs (extracellular S100 soil sensor receptors)-Fc fusion proteins work as prominent decoys to S100A8/A9-induced lung tropic cancer metastasis. (2018)
  • Author(s): Kinoshita R, Sato H, Yamauchi A, Takahashi Y, Inoue Y, Sumardika IW, Chen Y, Tomonobu N, Araki K, Shien K, Tomida S, Torigoe H, Namba K, Kurihara E, Ogoshi Y, Murata H, Yamamoto KI, Futami J, Putranto EW, Ruma IMW, Yamamoto H, Soh J, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M
  • Journal Title: Int J Cancer. Volume: - Issue: 12 Pages: 3138-3145
  • DOI: 10.1002/ijc.31945
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis. (2018)
  • Author(s): Kinoshita R, Sato H, Yamauchi A, Takahashi Y, Inoue Y, Sumardika IW, Chen Y, Tomonobu N, Araki K, Shien K, Tomida S, Torigoe H, Namba K, Kurihara E, Ogoshi Y, Murata H, Yamamoto KI, Futami J, Putranto EW, Ruma IMW, Yamamoto H, Soh J, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M.
  • Journal Title: Int J Cancer. Volume: 印刷中 Issue: 2 Pages: 569-575
  • DOI: 10.1002/ijc.31982
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Embigin Promotes Prostate Cancer Progression by S100A4-Dependent and-Independent Mechanisms. (2018)
  • Author(s): Ruma IMW, Kinoshita R, Tomonobu N, Inoue Y, Kondo E, Yamauchi A, Sato H, Sumardika IW, Chen Y, Yamamoto KI, Murata H, Toyooka S, Nishibori M, Sakaguchi M
  • Journal Title: Cancers (Basel) Volume: 10 Issue: 7 Pages: 239-239
  • DOI: 10.3390/cancers10070239
  • Peer Reviewed / Open Access
• [Journal Article] Tumor necrosis factor-α downregulates the REIC/Dkk-3 tumor suppressor gene in normal human skin keratinocytes (2018)
  • Author(s): Kataoka Ken、Maehara Natsumi、Ayabe Yuki、Murata Hitoshi、Huh Nam-Ho、Sakaguchi Masakiyo
  • Journal Title: Mol Med Rep. Volume: 17 Pages: 6661-6666
  • DOI: 10.3892/mmr.2018.8676
  • Peer Reviewed / Open Access
• [Journal Article] Signal Diversity of Receptor for Advanced Glycation End Products (2017)
  • Author(s): Sakaguchi M, Kinoshita R, Putranto EW, Ruma IMW, Sumardika IW, Youyi C, Tomonobu N, Yamamoto KI, Murata H.
  • Journal Title: Acta Medica Okayama Volume: 71 Issue: 6 Pages: 459-465
  • DOI: 10.18926/AMO/55582
  • NAID: 120006370709
  • URL: https://ousar.lib.okayama-u.ac.jp/55582
  • Peer Reviewed / Open Access
• [Journal Article] Robust cancer-specific gene expression by a novel cassette with hTERT and CMV promoter elements. (2017)
  • Author(s): Sakaguchi M, Sadahira T, Ueki H, Kinoshita R, Murata H, Yamamoto KI, Futami J, Nasu Y, Ochiai K, Kumon H, Huh NH, Watanabe M.
  • Journal Title: Oncology Reports Volume: 38 Issue: 2 Pages: 1108-1114
  • DOI: 10.3892/or.2017.5710
  • Peer Reviewed / Open Access
• [Journal Article] ｂ-1,3-galactosyl-O-glycosyl-glycoprotein ｂ-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. (2017)
  • Author(s): Sumardika I Wayan、Youyi Chen、Kondo Eisaku、Inoue Yusuke、Ruma I Made Winarsa、Murata Hitoshi、Kinoshita Rie、Yamamoto Ken-Ichi、Tomida Shuta、Shien Kazuhiko、Satoh Hiroki、Yamauchi Akira、Futami Junichiro、Putranto Endy Widya、Hibino Toshihiko、Toyooka Shinichi、Nishibori Masahiro、Sakaguchi Masakiyo
  • Journal Title: Oncology Reserch Volume: in press Issue: 3 Pages: 431-444
  • DOI: 10.3727/096504017x15031557924123
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] JNKによるリン酸化はSARM1のNAD分解活性を制御し、ミトコンドリア呼吸阻害を誘導する (2018)
  • Author(s): 村田等、山本健一、木下理恵、阪口政清
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] 分泌性S100A11-受容体RAGEシグナルを介した膵臓がん周辺微小環境における間質繊維芽細胞の増殖誘導の解明 (2018)
  • Author(s): 山本健一、高松仁志、友信奈保子、光井洋介、二見淳一郎、木下理恵、村田等、阪口政清
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] ミトコンドリア呼吸鎖複合体への作用を介したSARM1の神経細胞死誘導 (2017)
  • Author(s): 村田等、西川茜、高松仁志、山本健一、木下理恵、阪口政清
  • Organizer: 第90回日本組織培養学会大会
• [Presentation] 健常者及びパーキンソン病患者iPS細胞由来の神経細胞を用いたミトコンドリア機能解析 (2017)
  • Author(s): 村田等、山本健一、木下理恵、阪口政清
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] 神経細胞死・軸索変性に関与するSARM1のリン酸化制御 (2016)
  • Author(s): 村田等、西川茜、山本健一、木下理恵、阪口政清
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜市
  • Year and Date: 2016-11-30
• [Presentation] PINK1 regulation of mitochondrial homeostasis and cell survival. (2016)
  • Author(s): Murata H, Yamamoto K, Kinoshita R, Kataoka K, Huh NH, Sakaguchi M
  • Organizer: World congress on in vitro biology 2016
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-06-11
  • Int'l Joint Research / Invited
• [Presentation] Regulation of PINK1 expression under oxidative stress conditions. (2016)
  • Author(s): Murata H, Takamatsu H, Yamamoto K, Kinoshita R, Kataoka K, Huh NH, Sakaguchi M
  • Organizer: 第89回日本組織培養学会大会
  • Place of Presentation: 豊中市
  • Year and Date: 2016-05-25
• [Patent(Industrial Property Rights)] リン酸化SARM1、抗体、SARM1リン酸化阻害剤、神経変性疾患の予防又は治療薬、スクリーニング方法、SARM1改変体及び使用 (2017)
  • Inventor(s): 村田 等、阪口 政清、木下 理恵、山本 健一
  • Industrial Property Rights Holder: 岡山大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017-03-22
  • Overseas