新規オートファジーによる脳老化タンパク質調節機構の解析と創薬開発研究

• Project Area: Prevention of brain protein aging and dementia
• Project/Area Number: 15H01554
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 清水 重臣 東京医科歯科大学, 難治疾患研究所, 教授 (70271020)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000); Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2015: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 神経変性 / オートファジー / 脳老化 / 新規オートファジー / 神経変性疾患 / 脳老化変性タンパク質

Outline of Annual Research Achievements

オートファジーの多寡は、老化に伴って増えていく異常タンパク質の蓄積量に影響を与え、ひいては認知症などの発症に深く関わっている。本研究では、脳老化タンパク質の蓄積や認知症発症に、Atg5非依存的新規オートファジーが如何に関わっているかを明らかにするとともに、新規オートファジー調節を介した神経変性疾患治療法の開発研究を行なうことを目的としている。新規オートファジーとは、私たちのグループが発見した新しいタイプのオートファジーであり、Atg5やAtg7を使わずに実行されるオートファジーである。また、新規オートファジーは、酵母細胞から哺乳動物細胞まで種を越えて保存されていること、新規オートファジーとAtg5依存的オートファジーは役割を分担していること、赤血球の最終分化をはじめ様々な生理現象に関わっていることがわかっている。
今年度は、新規オートファジー実行分子の１種であるAag3分子を神経特異的に欠損させたマウスを作製し、詳細に解析した。その結果、（１）Atg5依存的オートファジーは正常に誘導されていること、（２）神経細胞に神経変性疾患を惹起しうる分子が蓄積していること、（３）神経細胞の脱落変性が生じ、神経変性疾患を発症していることを見出した。
また、Neuro2a細胞に種々の神経変性疾患原因分子を発現させ、新規オートファジー誘導化合物の中から、これらの蓄積分子を分解できる化合物を探索したところ、３種類の候補化合物の同定にいたった。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response. (2017)
  • Author(s): Kozaki T, Komano J, Kanbayashi D, Takahama M, Misawa T, Satoh T, Takeuchi O, Kawai T, Shimizu S, Matsuura Y, Akira S, Saitoh T
  • Journal Title: Proc Natl Acad Sci U S A Volume: 114 Issue: 10 Pages: 2681-2686
  • DOI: 10.1073/pnas.1621508114
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Autophagy suppresses cell migration by degrading GEF-H1, a RhoA GEF (2016)
  • Author(s): T. Yoshida, M. Tsujioka, S. Honda, S. Shimizu
  • Journal Title: Oncotarget Volume: 7 Issue: 23 Pages: 34420-9
  • DOI: 10.18632/oncotarget.8883
  • Peer Reviewed / Open Access
• [Journal Article] In Situ Characterization of Bak Clusters Responsible for Cell Death Using Single Molecule Localization Microscopy (2016)
  • Author(s): Y. Nasu, A. Benke, S. Arakawa, G. Yoshida, G. Kawamura, S. Manley, S. Shimizu, T. Ozawa
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 27505-27505
  • DOI: 10.1038/srep27505
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Golgi membrane-associated degradation pathway in yeast and mammals (2016)
  • Author(s): H. Yamaguchi, S. Arakawa, T. Kanaseki, T. Miyatsuka, Y. Fujitani, H. Watada, Y. Tsujimoto, S. Shimizu
  • Journal Title: EMBO J. Volume: 35 Issue: 18 Pages: 1991-2007
  • DOI: 10.15252/embj.201593191
  • Peer Reviewed
• [Journal Article] Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress‐induced autophagy (2016)
  • Author(s): S. Torii, T. Yoshida, S. Arakawa, S. Honda, A. Nakanishi, S. Shimizu
  • Journal Title: EMBO reports Volume: 11 Issue: 11 Pages: 1552-1564
  • DOI: 10.15252/embr.201642565
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Autophagy controls centrosome number by degrading Cep63. (2016)
  • Author(s): Watanabe Y, Honda S, Konishi A, Satoko Arakawa S, Murohashi M, Yamaguchi H, Torii S, Tanabe M, Tanaka S, Warabi E, Shimizu S.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 13508-13508
  • DOI: 10.1038/ncomms13508
  • NAID: 120007129257
  • Peer Reviewed / Open Access
• [Journal Article] A mild and facile synthesis of aryl and alkenyl sulfides via copper-catalyzed deborylthiolation of organoborons with thiosulfonates (2015)
  • Author(s): Suguru Yoshida, Yasuyuki Sugimura, Yuki Hazama, Yoshitake Nishiyama, Takahisa Yano, Shigeomi Shimizu, Takamitsu Hosoya
  • Journal Title: Chemical Communications Volume: 51 Issue: 93 Pages: 16613-16616
  • DOI: 10.1039/c5cc07463k
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of a novel compound that inhibits both mitochondria-mediated necrosis and apoptosis. (2015)
  • Author(s): S. Arakawa, I. Nakanomyo, Y. Kudo-Sakamoto, H. Akazawa, I. Komuro, S. Shimizu.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 467 Pages: 1006-11
  • Peer Reviewed
• [Journal Article] Direct Thioamination of Arynes via Reaction with Sulfilimines and Migratory N‐Arylation (2015)
  • Author(s): Suguru Yoshida, Takahisa Yano, Yoshihiro Misawa, Yasuyuki Sugimura, Kazunobu Igawa, Shigeomi Shimizu, Katsuhiko Tomooka, Takamitsu Hosoya
  • Journal Title: Journal of the American Chemical Society Volume: 137 Issue: 44 Pages: 14071-14074
  • DOI: 10.1021/jacs.5b10557
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Molecular mechanisms of Atg5-independent alternative autophagy (2016)
  • Author(s): Shimizu S
  • Organizer: Gordon Research Conference.
  • Place of Presentation: ロスアンジェルス（米国）
  • Year and Date: 2016-03-20
  • Int'l Joint Research
• [Presentation] Identification of natural product against fatty liver disease based on the induction of alternative autophagy (2016)
  • Author(s): Shimizu S
  • Organizer: ICNIM2016
  • Place of Presentation: Hotel Royton, Sapporo
  • Int'l Joint Research
• [Presentation] Alternative Autophagy is Essential for Neuronal Cell Maintenance (2016)
  • Author(s): Shimizu S
  • Organizer: Brain Protein Aging and Dementia Control International Workshop
  • Place of Presentation: Kakuyu Kaikan in Nagoya University, Nagoya
  • Int'l Joint Research
• [Presentation] Mitophagy and alternative autophagy (2016)
  • Author(s): Shimizu S
  • Organizer: The 13th Conference of Asian Society for Mitochondrial Research and Medicine
  • Place of Presentation: TKP Garden City Shinagawa, Shinagawa
  • Int'l Joint Research / Invited
• [Presentation] Macroautophagy mediates elimination of mitochondria from embryonic reticulocytes (2016)
  • Author(s): 清水重臣
  • Organizer: 第78回日本血液学会
  • Place of Presentation: パシフィコ横浜、横浜
  • Invited
• [Presentation] Biological Roles of Autophagic Cell Death (2015)
  • Author(s): Shimizu S
  • Organizer: Japan Australia Meeting on Cell Death
  • Place of Presentation: メルボルン（オーストラリア）
  • Year and Date: 2015-10-21
  • Int'l Joint Research / Invited
• [Presentation] Development of Small Compound against Polyglutamine Diseases based on the Regulation of Alternative Autophagy (2015)
  • Author(s): Shimizu S
  • Organizer: Brain Protein Aging and Dementia Control 1st InternationalSymposium
  • Place of Presentation: 野依記念学術交流館（愛知県・名古屋市）
  • Year and Date: 2015-10-09
  • Int'l Joint Research / Invited
• [Book] Innovative Medicine : Basic Research and Development (2015)
  • Author(s): shimizu S
  • Total Pages: 339
  • Publisher: Springer Press
• [Remarks] 病態細胞生物学分野ホームページ
  • URL: http://www.tmd.ac.jp/mri/pcb/index.html