Evaluation of involvement in neurodegeneration by collapse of mitochondrial DNA maintenance mechanism using iPS cells

• Project/Area Number: 15K15083
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Hiroshima University
• Principal Investigator: Morino Hiroyuki 広島大学, 原爆放射線医科学研究所, 准教授 (10397953)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 遺伝子 / 脳神経疾患 / ミトコンドリア

Outline of Final Research Achievements

We identified TWNK (C10orf2) as a new causative gene of Perrault syndrome. TWNK encodes mitochondrial DNA (mtDNA) helicase and is involved in mitochondrial maintenance mechanism. The purpose of this study is to reproduce the process of mutations of TWNK damaging the maintenance mechanism of mtDNA and leading to neuronal death by patient-derived iPS cells. Using the fact that mtDNA mutation is initialized when iPS cells are established, we observed the accumulation of mtDNA mutations in neurons differentiated from iPS cells. A cell-line that minimized mitochondrial abnormality was obtained and it was shown that mtDNA mutations accumutated due to TWNK mutations.

Research Products

• [Journal Article] PLK1-mediated phosphorylation of WDR62/MCPH2 ensures proper mitotic spindle orientation (2017)
  • Author(s): Miyamoto Tatsuo、Akutsu Silvia Natsuko、Fukumitsu Akihiro、Morino Hiroyuki、Masatsuna Yoshinori、Hosoba Kosuke、Kawakami Hideshi、Yamamoto Takashi、Shimizu Kenji、Ohashi Hirofumi、Matsuura Shinya
  • Journal Title: Human Molecular Genetics Volume: 26 Issue: 22 Pages: 4429-4440
  • DOI: 10.1093/hmg/ddx330
  • Peer Reviewed
• [Journal Article] First report of a Japanese family with spinocerebellar ataxia type 10: The second report from Asia after a report from China (2017)
  • Author(s): Naito Hiroyuki、Takahashi Tetsuya、Kamada Masaki、Morino Hiroyuki、Yoshino Hiroyo、Hattori Nobutaka、Maruyama Hirofumi、Kawakami Hideshi、Matsumoto Masayasu
  • Journal Title: PLOS ONE Volume: 12 Issue: 5 Pages: 0177955-0177955
  • DOI: 10.1371/journal.pone.0177955
  • Peer Reviewed / Open Access
• [Journal Article] Causative Genes for Amyotrophic Lateral Sclerosis (2016)
  • Author(s): Maruyama H, Morino H, Kawakami H
  • Journal Title: Brain Nerve Volume: 68 Pages: 1081-1086
  • NAID: 40020964548
  • Peer Reviewed
• [Journal Article] A mutation in the low voltage -gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. (2015)
  • Author(s): Morino H., Matsuda Y., Muguruma K., Miyamoto R., Ohsawa R., Ohtake T., Otobe R., Watanabe M., Maruyama H., Hashimoto K., Kawakami H.
  • Journal Title: Molecular Brain Volume: 8 Issue: 1 Pages: 1-9
  • DOI: 10.1186/s13041-015-0180-4
  • Peer Reviewed / Open Access
• [Journal Article] Exome sequencing identifies a novel intronic mutation in ENG that cause recurrence of pulmonary arteriovenous malformations. (2015)
  • Author(s): Kawarai T, Saji N, Miyamoto R, Sato T, Morino H, Orlacchio A, Oki R, Kimura K and Kaji R.
  • Journal Title: Journal of the Neurological Sciences Volume: 351 Issue: 1-2 Pages: 231-233
  • DOI: 10.1016/j.jns.2015.02.007
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 次世代シーケンスによる遺伝性神経変性疾患の原因遺伝子同定率 (2017)
  • Author(s): 森野豊之
  • Organizer: 第62回日本人類遺伝学会
• [Presentation] 低電位活性型CaチャンネルCACNA1Gの変異は脊髄小脳変性症の原因である (2016)
  • Author(s): 森野 豊之
  • Organizer: 第39回日本神経科学大会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] 優性遺伝性脊髄小脳変性症の新規原因遺伝子CACNA1Gの同定 (2016)
  • Author(s): 森野 豊之
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
• [Remarks] 原爆放射線医科学研究所 分子疫学研究分野
  • URL: http://home.hiroshima-u.ac.jp/epidem/index.html