Characterization of Parkinson's disease-associated protein CHCHD2 and its molecular signaling network

• Project/Area Number: 16K19525
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Juntendo University
• Principal Investigator: Meng Hongrui 順天堂大学, 医学(系)研究科(研究院), 博士研究員 (90736498)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: パーキンソン病 / 神経変性 / ミトコンドリア / CHCHD2 / alpha-Synuclein / CHCHD２

Outline of Final Research Achievements

Mutations in a mitochondrial protein, CHCHD2, have been identified in familial Parkinson’s disease (PD) cases. To understand the physiological and pathological roles of CHCHD2, we manipulated the expression of CHCHD2 in Drosophila and mammalian cells. The loss of CHCHD2 in Drosophila causes abnormal matrix structures and impaired oxygen respiration in mitochondria, leading to oxidative stress, dopaminergic neuron loss and motor dysfunction with age. These PD-associated phenotypes are rescued by the overexpression of human CHCHD2 but not its PD-associated mutants. CHCHD2 is upregulated by various mitochondrial stresses, including the destabilization of mitochondrial oxidative reaction and unfolded protein stress. CHCHD2 along with some molecular related to cell death signaling and mitochondria respiration, dynamically regulate mitochondrial oxidative phosphorylation and cell death in response to mitochondrial stress.

Academic Significance and Societal Importance of the Research Achievements

研究成果は、ミトコンドリアの機能低下によるストレスと細胞死シグナルの活性化の分子レベルでの病態機序、およびそれを改善する遺伝子が明らかになりました。本研究で得られるCHCHD2ネットワークのハブとなる遺伝子は、CHCHD2変異あるいはミトコンドリア関連の遺伝子変異によるPDの神経変性において中心的な役割を持つことが考えられる。これらは学問的なインパクトとともに、ネットワークのハブとなる遺伝子産物の挙動変化が、CHCHD2変異にリンクするPDや孤発性PDの診断と治療の分子標的としての意義を明らかにするものであり、臨床応用への発展が期待される。

Research Products

• [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
• [Journal Article] Loss of Parkinson's disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c. (2017)
  • Author(s): Meng H, Yamashita C, Shiba-Fukushima K, Inoshita T, Funayama M, Sato S, Hatta T, Natsume T, Umitsu M, Takagi J, Imai Y, Hattori N.
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 15500-15500
  • DOI: 10.1038/ncomms15500
  • Peer Reviewed / Open Access
• [Journal Article] Measurements of the mitochondrial respiration and glycolytic activity in Drosophila embryonic cells (2017)
  • Author(s): Meng Hongrui、Yamashita Chikara、Hattori Nobutaka、Imai Yuzuru
  • Journal Title: Protocol Exchange Volume: －
  • DOI: 10.1038/protex.2017.069
  • Open Access
• [Journal Article] Monitoring Mitochondrial Changes by Alteration of the PINK1-Parkin Signaling in Drosophila (2017)
  • Author(s): Tsuyoshi Inoshita, Kahori Shiba-Fukushima, Hongrui Meng, Nobutaka Hattori, Yuzuru Imai
  • Journal Title: Methods in Molecular Biology Volume: 印刷中 Pages: 1-11
  • DOI: 10.1007/7651_2017_9
  • ISBN: 9781493977499, 9781493977505
  • Peer Reviewed
• [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
• [Presentation] Loss of Parkinson’s disease-associated protein CHCHD2 affects mitochondrial cristae structure and facilitates cytochrome c release from mitochondria (2017)
  • Author(s): Meng Hongrui、Yamashita Chikara、Shiba-Fukushima Kahori、Inoshita Tsuyoshi、Imai Yuzuru、Hattori Nobutaka
  • Organizer: 日本神経学会学術大会
• [Presentation] The Loss of Parkinson's Disease-Associated Protein CHCHD2 Affects Mitochondrial Cristae Structure and Destabilizes Cytochrome c (2016)
  • Author(s): Hongrui Meng, Chikara Yamashita, Kahori Shiba, Tsuyoshi Inoshita, Manabu Funayama, Shigeto Sato, Yuzuru Imai, Nobutaka Hattori
  • Organizer: 第39 回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-12-01
• [Presentation] CHCHD２, a Parkinson’s-Disease Associated Protein, Regulates the Mitochondrial cristae integrity and function in Drosophila (2016)
  • Author(s): Hongrui Meng, Chikara Yamashita, Kahori Shiba, Tsuyoshi Inoshita, Yuzuru Imai, Nobutaka Hattori
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: 横浜
• [Presentation] Mutations of mitochondrial protein CHCHD2 lead to parkinson’s disease-like phenotypes in Drosophila (2016)
  • Author(s): Hongrui Meng, Chikara Yamashita, Kahori Shiba, Tsuyoshi Inoshita, Manabu Funayama, Shigeto Sato, Yuzuru Imai, Nobutaka Hattori
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸