Identification of Parkinson disease-specific mitochondrial pathogenesis for disease-modifying therapy

• Project/Area Number: 18KK0242
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Juntendo University
• Principal Investigator: Saiki Shinji 順天堂大学, 医学部, 先任准教授 (00339996)
• Co-Investigator(Kenkyū-buntansha): 笹澤 有紀子 順天堂大学, 大学院医学研究科, 特任助教 (20594922) ; 井本 正哉 慶應義塾大学, 理工学部(矢上), 教授 (60213253) ; 赤松 和土 順天堂大学, 大学院医学研究科, 教授 (60338184) ; 石川 景一 順天堂大学, 大学院医学研究科, 准教授 (90733973)
• Project Period (FY): 2018-10-09 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2020: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2019: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: パーキンソン病 / オートファジー / ミトコンドリア / 代謝 / iPS細胞 / ES細胞 / ポリアミン / ケミカルバイオロジー

Outline of Final Research Achievements

In terms of the pathogenesis of Parkinson's disease, dysfunction of lysosomal proteinases and mitochondria are identified as key molecular mechanisms. In this context, we explored potential therapeutic application of 7 candidate chemicals protecting mitochondria with ES cell-derived neurons (UK) and iPS cell-derived neurons (Japan). We identified nicotinamide to rescue NAD+ insufficiency due to autophagy insufficiency, resulting in protecting cell death via the mitochondria dependent mechanisms.

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病病態の中核をなすミトコンドリア機能障害に対して、NAD+レベルを上昇させることでミトコンドリア機能障害を回復させ、引いては細胞死を抑制するという全く新しい分子機構を持つ化合物nicotinamideを見出した。この作用点は新たなパーキンソン病治療標的となる可能性を秘めている。

Research Products

• [Int'l Joint Research] Newcastle大学(英国)
• [Journal Article] Metabolomic analysis data of MPP+-exposed SH-SY5Y cells using CE-TOFMS (2021)
  • Author(s): Amo Taku、Oji Yutaka、Saiki Shinji、Hattori Nobutaka
  • Journal Title: Data in Brief Volume: 34 Pages: 106707-106707
  • DOI: 10.1016/j.dib.2020.106707
  • Peer Reviewed / Open Access
• [Journal Article] A chemical genomics-aggrephagy integrated method studying functional analysis of autophagy inducers (2020)
  • Author(s): Kataura Tetsushi、Tashiro Etsu、Nishikawa Shota、Shibahara Kensuke、Muraoka Yoshihito、Miura Masahiro、Sakai Shun、Katoh Naohiro、Totsuka Misato、Onodera Masafumi、Shin-Ya Kazuo、Miyamoto Kengo、Sasazawa Yukiko、Hattori Nobutaka、Saiki Shinji、Imoto Masaya
  • Journal Title: Autophagy Volume: Aug 7 Issue: 8 Pages: 1-17
  • DOI: 10.1080/15548627.2020.1794590
  • Peer Reviewed / Open Access