Elucidation of pathogenic mechanism of Parkinson's disease through analysis of IPAS, a novel substrate of Parkin

• Project/Area Number: 26430051
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Torii Satoru 東京医科歯科大学, 難治疾患研究所, プロジェクト講師 (10444001)
• Co-Investigator(Renkei-kenkyūsha): SOGAWA Kazuhiro 東北大学, 生命科学研究科, 教授 (80175421) ; YASUMOTO Kenichi 東北大学, 生命科学研究科, 准教授 (90241629)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: IPAS / PINK1 / Parkin / リン酸化 / パーキンソン病 / ＰＩＮＫ１ / Ｐａｒｋｉｎ / 神経変性疾患 / MPTP

Outline of Final Research Achievements

In this study, we have shown that IPAS is regulated by the PINK1-Parkin pathway. IPAS was phosphorylated by PINK1 in a CCCP-dependent manner, bound to Parkin and eventually degraded. Furthermore, by analysis using tissues from patients of Parkinson’s disease, expression of IPAS was increased in substantia nigra in midbrain of these patients. In addition, MPTP-induced neuronal cell death in substantia nigra was decreased in IPAS knockout mice. These results suggest that IPAS accumulation induces neuronal cell death, leading to onset of Parkinson’s disease when regulation by PINK1 and Parkin is lost due to mutations.

Research Products

• [Journal Article] Identification of PPM1D as an essential Ulk1 phosphatase for genotoxic stress-induced autophagy (2016)
  • Author(s): Torii S, Yoshida T, Arakawa S, Honda S, Nakanishi A, Shimizu S
  • Journal Title: EMBO reports Volume: 17 Pages: 1552-1564
  • 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] Involvement of inhibitory PAS domain protein in neuronal cell death in Parkinson’s disease (2015)
  • Author(s): Satoru Torii, Shuya Kasai, Ayako Suzuki, Yuta Todoroki, Kazuma Yokosawa, Ken-ichi Yasumoto, Hiroshi Kiyonari, Yoshiko Mukumoto, Akiyoshi Kakita, Kazuhiro Sogawa
  • Journal Title: Cell Death Discovery Volume: １ Issue: 1 Pages: 1-12
  • DOI: 10.1038/cddiscovery.2015.15
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory PAS domain protein is a substrate of PINK1 and Parkin and mediates cell death in a Parkinson’s disease model (2015)
  • Author(s): Shuya Kasai, Satoru Torii, Akiyoshi Kakita, Kazuhiro Sogawa
  • Journal Title: Cell Death & Disease Volume: 6 Issue: 9 Pages: 1-3
  • DOI: 10.1038/cddis.2015.243
  • Open Access
• [Presentation] DNA傷害誘導性オートファジーを制御するPPM1D分子の役割 (2016)
  • Author(s): 鳥居暁, 吉田達士, 荒川聡子, 本田真也, 清水重臣
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] DNA傷害誘導性オートファジーを制御するPPM1D分子の役割 (2016)
  • Author(s): 鳥居暁, 吉田達士, 荒川聡子, 本田真也, 清水重臣
  • Organizer: 第10回オートファジー研究会
  • Place of Presentation: NASPAニューオータニ（新潟県南魚沼郡湯沢町）
  • Year and Date: 2016-11-13
• [Presentation] オルタナティブオートファジーのケミカルバイオロジー (2014)
  • Author(s): 鳥居暁、室橋道子、荒川聡子、桜井一、清水重臣
  • Organizer: 第8回オートファジー学会
  • Place of Presentation: 日本、札幌
  • Year and Date: 2014-11-09 – 2014-11-11