Loss of mitochondria quality control induce dopaminergic neurodegeneration

• Project/Area Number: 19K07850
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Juntendo University
• Principal Investigator: Sato Shigeto 順天堂大学, 医学部, 先任准教授 (00445537)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: パーキンソン病 / ミトコンドリア / ドーパミン細胞 / 神経変性 / Parkin / CHCHD2 / モデルマウス / 神経細胞死 / WDR45 / モデル動物 / ドーパミン / マウス

Outline of Research at the Start

本研究では、パーキンソン病発症機序におけるミトコンドリア障害説の解を求めるため、ミトコンドリア可視化の技術を応用した動物モデル作成、および神経細胞での変異ミトコンドリアの動態解析を行うことを目的とする。これによる、パーキンソン病モデルマウスの確立は変異ミトコンドリアを生み出す根本原因(内的要因)の探索をも可能とし、老化や孤発性パーキンソン病の実態に迫ることが期待される。

Outline of Final Research Achievements

Parkin knockout mice and CHCHD2 knockout mice showed motor symptoms and dopaminergic neuronal loss over the age of 100 weeks. Fragmented and damaged mitochondria accumulated in the substantia nigra dopaminergic cells in the aged mice, suggesting that increased vulnerability of dopaminergic cells is involved in neuronal cell death.

Academic Significance and Societal Importance of the Research Achievements

モデルマウスの解析から不良なミトコンドリアの蓄積がパーキンソン病の原因であることが有力となり、古くから指摘されてきたミトコンドリア障害説を裏付ける結果となった。このモデルマウスの利用はミトコンドリアをターゲットとした治療法の開発に有益である。

Research Products

• [Journal Article] Homeostatic p62 levels and inclusion body formation in CHCHD2 knockout mice (2021)
  • Author(s): Sato S, Noda S, Torii S, Amo T, Ikeda A, Funayama M, Yamaguchi J, Fukuda T, Kondo H, Tada N, Arakawa S, Watanabe M, Uchiyama Y, Shimizu S, Hattori N
  • Journal Title: Hum Mol Genet. Volume: 30 Pages: 443-453
  • Peer Reviewed / Open Access
• [Journal Article] PARKIN modifies peripheral immune response and increases neuroinflammation in active experimental autoimmune encephalomyelitis (EAE) (2021)
  • Author(s): Cossu D, Yokoyama K, Sato S, Noda S, Sechi LA, Hattori N.
  • Journal Title: J Neuroimmunol. Volume: 359 Pages: 577694-577694
  • Peer Reviewed / Open Access
• [Journal Article] Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice (2020)
  • Author(s): Noda S, Sato S, Fukuda T, Tada N, Uchiyama Y, Tanaka K, Hattori N
  • Journal Title: Neurobiol Dis. Volume: 136 Pages: 104717-104717
  • Peer Reviewed / Open Access
• [Journal Article] Variants in saposin D domain of prosaposin gene linked to Parkinson's disease. (2020)
  • Author(s): Oji Y, Hatano T, Ueno SI, Funayama M, Ishikawa KI, Okuzumi A, Noda S, Sato S, Satake W, Toda T, Li Y, Hino-Takai T, Kakuta S, Tsunemi T, Yoshino H, Nishioka K, Matsuda J, Hattori N
  • Journal Title: Brain Volume: 143 Pages: 1190-1205
  • Peer Reviewed / Open Access
• [Journal Article] Aging-related motor function and dopaminergic neuronal loss in C57BL/6 mice. (2020)
  • Author(s): Noda S, Sato S, Fukuda T, Tada N, Hattori N
  • Journal Title: Mol Brain. Volume: 13 Pages: 46-46
  • Peer Reviewed / Open Access
• [Journal Article] Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice. (2020)
  • Author(s): Noda S, Sato S, Fukuda T, Tada N, Uchiyama Y, Tanaka K, Hattori N.
  • Journal Title: Neurobiol Dis. Volume: 136 Pages: 104717-104717
  • DOI: 10.1016/j.nbd.2019.104717
  • Peer Reviewed / Open Access
• [Patent(Industrial Property Rights)] パーキンソン病モデル非ヒト動物 (2019)
  • Inventor(s): 佐藤栄人、野田幸子、服部信孝
  • Industrial Property Rights Holder: 佐藤栄人、野田幸子、服部信孝
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-154898
  • Filing Date: 2019