Development of novel cellular models for Parkinson's disease focusing on energy-homeostasis

• Project/Area Number: 16K09676
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Juntendo University
• Principal Investigator: FUNAYAMA Manabu 順天堂大学, 医学部, 准教授 (70468578)
• Research Collaborator: AMO taku ; AKAMATSU wado
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: パーキンソン病 / ミトコンドリア / 電子伝達系 / 遺伝子 / iPS細胞 / ノックアウト細胞 / 酸化ストレス / 複合体IV / ATP / 酸素呼吸 / iPS / ドーパミン神経細胞 / 分化 / メタボロミクス / 機能喪失 / 細胞モデル / 解糖系 / エネルギー代謝

Outline of Final Research Achievements

We recently identified coiled-coil-helix coiled-coil-helix domain containing 2 (CHCHD2) mutations are novel causes for autosomal dominant Parkinson’s disease (PD). Although CHCHD2 is localized to mitochondria and involved in mitochondrial complex IV, its function remains largely unknown. To elucidate the role of CHCHD2 in mitochondria, we generated CHCHD2 knockout SH-SY5Y neuroblastoma cells (CHCHD2-KO) and induced pluripotent stem cells (iPSc) derived from PD patient with CHCHD2 T61I mutation.
CHCHD2-KO as well as iPS showed a profound mitochondrial dysfunction, suggesting that CHCHD2 plays a crucial role in maintaining normal mitochondrial function. These findings indicate that CHCHD2 cellular models are a useful model for understanding CHCHD2 function and pathophysiology of CHCHD2 mutations and PD.

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病 (PD) とミトコンドリア機能低下は数十年来指摘されているが、家族性PDの原因遺伝子で直接ミトコンドリア電子伝達系に関与している遺伝子はCHCHD2のみである。本研究で開発したCHCHD2細胞モデル (ノックアウト細胞およびPD患者iPS細胞) に共通してミトコンドリア電子伝達系の機能低下が見出され、この表現型を指標としたPDの病態解明や新規治療薬の開発への貢献が期待される。

Research Products

• [Journal Article] Clinical heterogeneity of frontotemporal dementia and Parkinsonism linked to chromosome 17 caused by MAPT N279K mutation in relation to tau positron emission tomography features (2019)
  • Author(s): Ikeda Aya、Shimada Hitoshi、Nishioka Kenya、Takanashi Masashi、Hayashida Arisa、Li Yuanzhe、Yoshino Hiroyo、Funayama Manabu、Ueno Yuji、Hatano Taku、Sahara Naruhiko、Suhara Tetsuya、Higuchi Makoto、Hattori Nobutaka
  • Journal Title: Movement Disorders Volume: 34 Issue: 4 Pages: 568-574
  • DOI: 10.1002/mds.27623
  • Peer Reviewed / Open Access
• [Journal Article] GCH1 mutations in dopa-responsive dystonia and Parkinson's disease. (2018)
  • Author(s): Yoshino H, Nishioka K, Li Y, Oji Y, Oyama G, Hatano T, Machida Y, Shimo Y, Hayashida A, Ikeda A, Mogushi K, Shibagaki Y, Hosaka A, Iwanaga H, Fujitake J, Ohi T, Miyazaki D, Sekijima Y, Oki M, Kusaka H, Fujimoto KI Ugawa Y, Funayama M, Hattori N.
  • Journal Title: Journal of Neurology Volume: 265(8) Issue: 8 Pages: 1860-1870
  • DOI: 10.1007/s00415-018-8930-8
  • Peer Reviewed / Open Access
• [Journal Article] Isolated nigral degeneration without pathological protein aggregation in autopsied brains with LRRK2 p.R1441H homozygous and heterozygous mutations (2018)
  • Author(s): Takanashi M, Funayama M (Contributed equally), Matsuura E, Yoshino H, Li Y, Tsuyama S, Takashima H, Nishioka K, Hattori N
  • Journal Title: Acta Neuropathologica Communications Volume: 6 Issue: 1 Pages: 105-105
  • DOI: 10.1186/s40478-018-0617-y
  • Peer Reviewed / Open Access
• [Journal Article] Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease. (2018)
  • Author(s): Fujimaki M, Saiki S, Li Y, Kaga N, Taka H, Hatano T, Ishikawa KI, Oji Y, Mori A, Okuzumi A, Koinuma T, Ueno SI, Imamichi Y, Ueno T, Miura Y, Funayama M, Hattori N.
  • Journal Title: Neurology. Volume: 90 Issue: 5 Pages: 1-8
  • DOI: 10.1212/wnl.0000000000004888
  • Peer Reviewed / Open Access
• [Journal Article] Genetic analysis of TMEM230 in Japanese patients with familial Parkinson’s disease. (2018)
  • Author(s): Conedera SA, Li Y, Funayama M, Yoshino H, Nishioka K, Hattori N.
  • Journal Title: Parkinsonism Relat Disord Volume: 48 Pages: 107-108
  • DOI: 10.1016/j.parkreldis.2017.12.020
  • Peer Reviewed
• [Journal Article] COQ2 variants in Parkinson's disease and multiple system atrophy. (2018)
  • Author(s): Mikasa M, Kanai K, Li Y, Yoshino H, Mogushi K, Hayashida A, Ikeda A, Kawajiri S, Okuma Y, Kashihara K, Sato T, Kondo H, Funayama M, Nishioka K, Hattori N.
  • Journal Title: J Neural Transm (Vienna) Volume: - Issue: 6 Pages: 938-944
  • DOI: 10.1007/s00702-018-1885-1
  • Peer Reviewed / Open Access
• [Journal Article] A novel mutation of CHCHD2 p.R8H in a sporadic case of Parkinson's disease (2017)
  • Author(s): Ikeda, Aya; Matsushima, Takashi; Daida, Kensuke; Nakajima, Sho; Conedera, Silvio; Li, Yuanzhe; Yoshino, Hiroyo; Oyama, Genko; Funayama, Manabu; Nishioka, Kenya; Hattori, Nobutaka
  • Journal Title: PARKINSONISM & RELATED DISORDERS Volume: 34 Pages: 66-68
  • DOI: 10.1016/j.parkreldis.2016.10.018
  • Peer Reviewed
• [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] Mutation screening of PLA2G6 in Japanese patients with early onset dystonia-parkinsonism. (2017)
  • Author(s): Yamashita C, Funayama M, Li Y, Yoshino H, Yamada H, Seino Y, Tomiyama H, Hattori N.
  • Journal Title: J Neural Transm Volume: 4 Issue: 4 Pages: 431-435
  • DOI: 10.1007/s00702-016-1658-7
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] FBXO7 mutations in Parkinson's disease and multiple system atrophy. (2016)
  • Author(s): Conedera S, Apaydin H, Li Y, et al.
  • Journal Title: Neurobiol Aging. Volume: 40 Pages: 192.e1-192.e5
  • DOI: 10.1016/j.neurobiolaging.2016.01.003
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Schizophrenia as a prodromal symptom in a patient harboring SNCA duplication. (2016)
  • Author(s): Takamura S, Ikeda A, Nishioka K, Furuya H, Tashiro M, Matsushima T, Li Y, Yoshino H, Funayama M, Morinobu S, Hattori N.
  • Journal Title: Parkinsonism Relat Disord. Volume: S1353-8020 Pages: 30028-1
  • DOI: 10.1016/j.parkreldis.2016.01.028
  • Peer Reviewed / Open Access
• [Journal Article] Lysosomal storage of subunit c of mitochondrial ATP synthase in brain-specific ATP13a2-deficient mice (2016)
  • Author(s): Sato, S., Koike, M., Funayama, M., Ezaki, J., Fukuda, T., Ueno, T., Uchiyama, Y., Hattori, N
  • Journal Title: Am. J. Pathol. Volume: 186 Issue: 12 Pages: 3074-3082
  • DOI: 10.1016/j.ajpath.2016.08.006
  • Peer Reviewed
• [Journal Article] Genotype-phenotype correlations of cysteine replacement in CADASIL. (2016)
  • Author(s): Matsushima T, Conedera S, Tanaka R, Li Y, Yoshino H, Funayama M, Ikeda A, Hosaka Y, Okuzumi A, Shimada Y, Yamashiro K, Motoi Y, Nishioka K, Hattori N
  • Journal Title: Neurobiology of Aging Volume: 50
  • Peer Reviewed
• [Presentation] パーキンソン病の分子遺伝学研究 (2018)
  • Author(s): 舩山学
  • Organizer: 第59回日本神経学会学術大会
  • Invited
• [Presentation] A novel mutation of LRRK2 p.V1447M in familial Parkinson's disease (2018)
  • Author(s): 池田彩, 吉野浩代, 大山彦光, 吉田亘佑, 木村隆, 木谷光博, 沼尾文香, 鈴木圭輔, 卜部貴夫, 中山宜昭, 伊東秀文, 菅野直人, 河野智, 宮嶋裕明, 木村活生, 上田直久, 田中 章景, 舩山 学, 西岡 健弥, 服部信孝
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] Novel Parkinson’s disease families with LRRK2 p.R1441H homozygous and heterozygous mutation in Makurazaki region (2018)
  • Author(s): Yoshino H, Takanashi M, Funayama M, Matsuura E, Li Y, Tsuyama S, Takashima T, Nishioka K, Hattori N
  • Organizer: 日本人類遺伝学会 第63回大会
• [Presentation] Brain pathology, functional analysis and fly models of CHCHD2 p.T61I (2018)
  • Author(s): Nishioka K, Ikeda A, Meng H, Takanashi M, Yoshino H, Li Y, Imai Y, Funayama M, Hattori N
  • Organizer: Genetic Epidemiology of Parkinson's Disease 2018
  • Int'l Joint Research
• [Presentation] CHCHD2 DEFICIENCY LEADS TO MITOCHONDRIAL DYSFUNCTION AND INCREASING OXIDATIVE STRESS IN HUMAN NEUROBLASTOMA SH-SY5Y CELLS. (2017)
  • Author(s): unayama M, Park JS, Amo T, Funayama T, Akamatsu W, Sue CM, Hattori N.
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] A novel variant of CHCHD2 in a patient with sporadic Parkinson's disease. (2017)
  • Author(s): Funayama M, Ikeda A, Matsushima T, Daida S, Nakajima S, Conedera S, Li Y, Yoshino H, Oyama G, Nishioka K, Hattori N.
  • Organizer: 日本人類遺伝学会第62階大会
• [Presentation] CHCHD2 is novel gene for autosomal dominant Parkinson’s disease (2016)
  • Author(s): Funayama M, Hattori N
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: 京都国際会館 (京都府京都市)
  • Int'l Joint Research
• [Presentation] CHCHD2 is Novel Causative Gene for Autosomal Dominant Parkinson’s Disease (2016)
  • Author(s): 舩山学, 服部信孝
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: パシフィコ横浜 (神奈川県横浜市)
  • Invited
• [Remarks] 脳神経内科紹介 研究紹介【研究実績・研究内容】
  • URL: http://www.juntendo-neurology.com/n-kenkyu-syoukai.html
• [Remarks] 順天堂大学プレスリリース
  • URL: http://www.juntendo.ac.jp/news/20170607-01.html
• [Remarks] 順天堂大学医学部脳神経内科ホームページ
  • URL: http://www.juntendo-neurology.com