新規パーキンソン病・本態性振戦原因遺伝子のゲノム解析と分子病態解析

• Project Area: Personal genome-based initiatives toward understanding bran diseases
• Project/Area Number: 25129707
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Juntendo University
• Principal Investigator: 舩山 学 順天堂大学, 医学部, 准教授 (70468578)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥10,530,000 (Direct Cost: ¥8,100,000、Indirect Cost: ¥2,430,000); Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: パーキンソン病 / 遺伝子 / 感受性遺伝子 / ミトコンドリア

Outline of Annual Research Achievements

新規遺伝性パーキンソン病原因遺伝子を単離する目的で、常染色体優性遺伝性パーキンソン病の大家系について次世代シークエンサーをもちいたゲノム解析を実施した。その結果、coiled-coil-helix-coiled- coil-helix domain containing 2 (CHCHD2) 遺伝子 182C>T (Thr61Ile) 変異を同定した。340家系の常染色体優性遺伝性パーキンソン病患者についてCHCHD2遺伝子配列を解析した結果、発端家系に加え3家系からCHCHD2遺伝子変異を同定した。さらに孤発性パーキンソン病患者517症例、および健常対照者559例のCHCHD2遺伝子配列を比較した結果、CHCHD2遺伝子領域内にある2つの多型 (-9T>G、および5C>T) が患者群で有意に頻度が高かった (オッズ比2.51; P=0.0004、およびオッズ比4.69; P=0.0025)。したがってCHCHD2は稀な遺伝性パーキンソン病の原因遺伝子であるだけで無く、一般的な孤発性パーキンソン病の発症感受性遺伝子にもなりうることが本研究から明らかになった。CHCHD2はミトコンドリア電子伝達系に関与する分子であり、ミトコンドリア機能異常がパーキンソン病の病態の1つであると考えられていることからCHCHD2は新たなパーキンソン病治療ターゲットになりうることが強く示唆される。以上の結果をまとめ論文として発表した。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] ABCG2 variant has opposing effects on onset ages of Parkinson's disease and gout. (2015)
  • Author(s): Matsuo H, Tomiyama H, Satake W, Chiba T, Onoue H, Kawamura Y, Nakayama A, ShimizuS, Sakiyama M, Funayama M, Nishioka K, Shimizu T, Kaida K, Kamakura K, Toda T, Hattori N, ShinomiyaN.
  • Journal Title: Ann Clin Transl Neurol Volume: 2 Issue: 3 Pages: 302-306
  • DOI: 10.1002/acn3.167
  • Peer Reviewed / Open Access
• [Journal Article] Target- and input-dependent organization of AMPA and NMDA receptors in synaptic connections of the cochlear nucleus (2015)
  • Author(s): Rubio ME, Fukazawa Y, Kamasawa N, Clarkson C, Molnar E, Shigemoto R
  • Journal Title: J Comp Neurol Volume: 588 Pages: 29-35
  • DOI: 10.1016/j.neulet.2014.12.052
  • Peer Reviewed / Open Access
• [Journal Article] High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism. (2015)
  • Author(s): Nishioka K, Oyama G, Yoshino H, Li Y, Matsushima T, Takeuchi C, Mochizuki Y, Mori-Yoshimura M, Murata M, Yamasita C, Nakamura N, Konishi Y, Ohi K, Ichikawa K, Terada T, Obi T, Funayama M, Saiki S, Hattori N.
  • Journal Title: Neurobiol Aging. Volume: S0197 Issue: 5 Pages: 54-58
  • DOI: 10.1016/j.neurobiolaging.2015.01.020
  • Peer Reviewed
• [Journal Article] CHCHD2 mutations in autosomal dominant late-onset Parkinson’s disease: a genome-wide linkage and sequencing study. (2015)
  • Author(s): Funayama M, Ohe K, Amo T, Furuya N, Yamaguchi J, Saiki S, Yuanzhe L, Ogaki K, Ando M, Yoshinon H, Tomiyama H, Nishioka K, Hasegawa K, Saiki H, Satake W, Mogushi K, Sasaki R, Kokubo Y, Kuzuhara S, Toda T, Mizuno Y, Uchiyama Y, Ohno K, Hattori N.
  • Journal Title: Lancet Neurol Volume: 14 Issue: 3 Pages: 274-282
  • DOI: 10.1016/s1474-4422(14)70266-2
  • Peer Reviewed / Open Access
• [Journal Article] EIF4G1 gene mutations are not a common cause of Parkinson's disease in the Japanese population (2014)
  • Author(s): Nishioka K, Funayama M, Vilarino-GuellC, Ogaki K, Li Y, Sasaki R, Kokubo Y, Kuzuhara S, Kachergus JM, Cobb SA, Takahashi H, Mizuno Y, Farrer MJ, Ross OA, Hattori N
  • Journal Title: Parkinsonism Relat Disord. Volume: 20 Issue: 6 Pages: 659-61
  • DOI: 10.1016/j.parkreldis.2014.03.004
  • Peer Reviewed
• [Journal Article] Identification of a Japanese family with LRRK2 p.R1441G-related Parkinson's disease. (2014)
  • Author(s): Hatano T, Funayama M, Kubo S, Mata IF, Oji Y, Mori A, Zabetian CP, Waldherr SM, Yoshino H, Oyama G, Shimo Y, Fujimoto K, Oshima H, Kunii Y, Yabe H, Mizuno Y, Hattori N.
  • Journal Title: Neurobiol Aging. Volume: Nov;35(11) Issue: 11 Pages: 2656.e17-2656.e23
  • DOI: 10.1016/j.neurobiolaging.2014.05.025
  • Peer Reviewed
• [Journal Article] Juvenile-onset parkinsonism with digenic parkin and PINK1 mutations treated with subthalamic nucleus stimulation at 45 years after disease onset. (2014)
  • Author(s): Nakahara K, Ueda M, Yamada K, Koide T, Yoshimochi G, Funayama M, Kim JH, Yamakawa S, Mori A, Misumi Y, Uyama E, Hattori N, Ando Y.
  • Journal Title: J Neurol Sci. Volume: 15 Issue: 1-2 Pages: 276-277
  • DOI: 10.1016/j.jns.2014.07.053
  • Peer Reviewed
• [Journal Article] Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease. (2014)
  • Author(s): Li Y, Sekine T, Funayama M, Li L, Yoshino H, Nishioka K, Tomiyama H, Hattori N
  • Journal Title: Neurobiol Aging. Volume: 35 Issue: 4 Pages: 935.e3-935.e8
  • DOI: 10.1016/j.neurobiolaging.2013.09.019
  • Peer Reviewed
• [Journal Article] The evaluation of polyglutamine repeats in autosomal dominant Parkinson's disease. (2014)
  • Author(s): Yamashita C, Tomiyama H, Funayama M, Inamizu S, Ando M, Li Y, Yoshino H, Araki T, Ichikawa T, Ehara Y, Ishikawa K, Mizusawa H, Hattori N.
  • Journal Title: Neurobiol Aging. Volume: 35 Issue: 7 Pages: 1779.e17-1779.e21
  • DOI: 10.1016/j.neurobiolaging.2014.01.022
  • Peer Reviewed / Open Access
• [Journal Article] A case of α-synuclein gene duplication presenting with head-shaking movements. (2013)
  • Author(s): Itokawa K, Sekine T, Funayama M, Tomiyama H, Fukui M, Yamamoto T, Tamura N, Matsuda H, Hattori N, Araki N.
  • Journal Title: Mov Disord. Volume: 28 Issue: 3 Pages: 384-387
  • DOI: 10.1002/mds.25243
  • Peer Reviewed
• [Journal Article] Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, andCBS (2013)
  • Author(s): Ogaki K
  • Journal Title: Parkinsonism & Related Disorders Volume: 19 Issue: 1 Pages: 15-20
  • DOI: 10.1016/j.parkreldis.2012.06.019
  • Peer Reviewed
• [Journal Article] ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons. (2013)
  • Author(s): Matsui H, Sato F, Sato S, Koike M, Taruno Y, Saiki S, Funayama M, Ito H, Taniguchi Y, Uemura N, Toyoda A, Sakaki Y, Takeda S, Uchiyama Y, Hattori N, Takahashi R.
  • Journal Title: FEBS Lett Volume: 587(9) Issue: 9 Pages: 1316-1325
  • DOI: 10.1016/j.febslet.2013.02.046
  • Peer Reviewed / Open Access
• [Presentation] 日本人パーキンソン病におけるEIF4G1遺伝子変異の頻度. (2014)
  • Author(s): 舩山 学, 西岡 健弥, 大垣 光太郎, 李 元哲, 佐々木 良元, 小久保 康昌, 葛原 茂樹, 高橋 裕秀, 富山 弘幸, 水野 美邦, 服部 信孝.
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際センター
  • Year and Date: 2014-05-23
• [Presentation] 日本人パーキンソン病におけるVPS35 D620N変異の同定. (2013)
  • Author(s): 舩山学、安藤真矢、李元哲、柏原健一、村上善勇、石津暢隆、豊田千純子、野口克彦、橋本貴司、中野直樹、佐々木良元、小久保康昌、葛原茂樹、大垣光太郎、山下力、吉野浩代、波田野琢、富山弘幸、服部信孝.
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 東京
• [Remarks] 遺伝性パーキンソン病の原因遺伝子を新たに発見
  • URL: http://www.juntendo.ac.jp/graduate/pdf/news15.pdf
• [Patent(Industrial Property Rights)] パーキンソン病の診断 (2014)
  • Inventor(s): 服部信孝、舩山学
  • Industrial Property Rights Holder: 服部信孝、舩山学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-228827
  • Filing Date: 2014-11-11