Analysis of the molecular mechanism by which mitochondrial dysfunction leads to alpha-Synaclein aggregation

• Project/Area Number: 18K15465
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Juntendo University
• Principal Investigator: Meng Hongrui 順天堂大学, 医学(系)研究科(研究院), 特任助教 (90736498)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: パーキンソン病 / α-synuclein / ミトコンドリア / CHCHD2 / α-Synuclein

Outline of Final Research Achievements

Parkinson’s disease (PD) is characterized by the accumulation of aggregated α-synuclein into intraneuronal Lewy bodies (LBs). Mitochondrial dysfunction has been strongly implicated in the pathogenesis of PD. Our studies have shown that the missense mutation, T61I, in the familial PD-associated mitochondrial protein CHCHD2 causes mitochondrial dysfunction, exacerbating misfolded α-synuclein aggregation and LB formation. Using Drosophila harboring CHCHD2 T61I mutation and dopaminergic neuron cultures prepared from a PD patient with CHCHD2 T61I, we investigated the mechanism underlying the mitochondrial dysfunction-induced α-synuclein aggregation. Our in vivo and in vitro models characterized here will contribute to the understanding of the mechanism whereby mitochondrial dysfunction could be a risk factor for α-synuclein aggregation in the pathogenesis of PD.

Academic Significance and Societal Importance of the Research Achievements

CHCHD2変異によりα-synucleinが顕著に凝集・蓄積することが、病理解析で明らかとなった。患者由来のiPS細胞とミトコンドリア変性を再現するモデルハエを作製し、ミトコンドリア異常がα-synucleinの凝集化を導く現象を再現できた。今後、ミトコンドリアの機能異常がいかにα-synucleinの凝集化を導くか、その分子機序を解明することにより、予防的、治療的対策が可能になると期待される。老人性神経変性疾患に関しては、不溶性タンパク質の蓄積を削減に未然に防ぐことが最も効果的かつ経済的な対処法と考えられ、本研究で解析したモデル動物はその開発に貢献する。

Research Products

• [Journal Article] Mutations in CHCHD2 cause α-synuclein aggregation (2019)
  • Author(s): Ikeda A., Nishioka K., Meng H., Takanashi M., Hasegawa I., Inoshita T., Shiba-Fukushima K., Li Y., Yoshino H., Mori A., Okuzumi A., Yamaguchi A., Nonaka R., Izawa N., Ishikawa K.I., Saiki H., Morita M., Hasegawa M., Hasegawa K., Elahi M., et al.
  • Journal Title: Human Molecular Genetics Volume: 28 Issue: 23 Pages: 3895-3911
  • DOI: 10.1093/hmg/ddz241
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Parkinson's disease-associated iPLA2-VIA/PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling. (2019)
  • Author(s): Mori A, Hatano T, Inoshita T, Shiba-Fukushima K, Koinuma T, Meng H, Kubo SI, Spratt S, Cui C, Yamashita C, Miki Y, Yamamoto K, Hirabayashi T, Murakami M, Takahashi Y, Shindou H, Nonaka T, Hasegawa M, Okuzumi A, Imai Y, Hattori N.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 116(41) Issue: 41 Pages: 20689-20699
  • DOI: 10.1073/pnas.1902958116
  • NAID: 120007132272
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Light-driven activation of mitochondrial proton-motive force improves motor behaviors in a Drosophila model of Parkinson's disease. (2019)
  • Author(s): Imai Y, Inoshita T, Meng H, Shiba-Fukushima K, Hara KY, Sawamura N, Hattori N.
  • Journal Title: Commun Biol. Volume: 2 Issue: 1 Pages: 424-424
  • DOI: 10.1038/s42003-019-0674-1
  • Peer Reviewed
• [Journal Article] Twin CHCH Proteins, CHCHD2, and CHCHD10: Key Molecules of Parkinson’s Disease, Amyotrophic Lateral Sclerosis, and Frontotemporal Dementia (2019)
  • Author(s): Imai Yuzuru、Meng Hongrui、Shiba-Fukushima Kahori、Hattori Nobutaka
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 4 Pages: 908-908
  • DOI: 10.3390/ijms20040908
  • Peer Reviewed / Open Access
• [Presentation] CHCHD2変異がα-シヌクレインの凝集化を促進する (2019)
  • Author(s): 孟 紅蕊、井下 強、柴-福島 佳保里、池田 彩、西岡 健弥、今居 譲、服部 信孝
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 生体膜恒常性の変調によるα-Synuclein凝集メカニズム (2019)
  • Author(s): 今居 譲、森 暁生、井下 強、柴-福島 佳保里、孟 紅蕊、服部 信孝
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Mutations of CHCHD2 accelerate α-synuclein aggregation, conferring a prion-like seeding property to α-synuclein (2019)
  • Author(s): Meng H, Ikeda A, Nishioka K, Takanashi M, Inoshita T, Shiba-Fukushima K, Okuzumi A, Funayama M, Imai Y, Hattor N
  • Organizer: 第42回日本神経学会学術大会
• [Presentation] Analyses of CHCHD2 pathophysiology by human brain, iPSC and Drosophila model (2019)
  • Author(s): Ikeda A, Meng H, Nishioka K, Takanashi M, Li Y, Yoshino H, Inoshita T, Shiba-Fukushima K, Okuzumi A, Mori A, Yamaguchi A, Nonaka R, Izawa N, Ishikawa KI, Saiki H, Morita M, Funayama M, Hasegawa M, Okano H, Akamatsu W, Imai Y, Hattori N
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Mutations of CHCHD2 exacerbate α-synuclein accumulation in Drosophila (2018)
  • Author(s): 孟 紅蕊
  • Organizer: 第41回日本分子生物学会