Uncovering the pathophysiological mechanisms of neurodevelopmental disorders associated with ribosomopathies using Drosophila

• Project/Area Number: 18K07796
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Chiyonobu Tomohiro 京都府立医科大学, 医学(系)研究科(研究院), 助教 (40571659)
• Co-Investigator(Kenkyū-buntansha): 吉田 英樹 京都工芸繊維大学, 応用生物学系, 准教授 (30570600)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 神経発達症 / リボソーム / ショウジョウバエ / リボソーム病

Outline of Final Research Achievements

Genetic defects in ribosome biogenesis result in a group of diseases called ribosomopathies. Patients with ribosomopathies manifest multiorgan phenotypes, including neurodevelopmental disorders (NDDs). A well-characterized ribosomopathy, Shwachman-Diamond syndrome (SDS), is mainly associated with loss-of-function mutations in SBDS. In the present study, we investigated the phenotypes of Drosophila melanogaster following knockdown of the Drosophila ortholog of SBDS, CG8549, to directly study the neurological consequences. The pan-neuron-specific knockdown of CG8549 results in learning impairments, locomotive disabilities, hyperactivity, mechanically induced seizures, and anatomical defects in presynaptic terminals. Screening genes that interact with CG8549 by using this model will contribute to a better understanding of the pathogenesis of NDDs induced by defects in ribosomal biogenesis.

Academic Significance and Societal Importance of the Research Achievements

近年、神経発達症の病態としてリボソーム機能障害が着目されているが、神経症状に着目したリボソーム病のモデル生物はこれまでに報告がない。本研究で確立したショウジョウバエモデルは、リボソーム障害による神経発達症の新規治療探索研究に応用できると考えられ、学術的に意義の高い結果と考えている。

Research Products

• [Journal Article] A novel Drosophila model for neurodevelopmental disorders associated with Shwachman-Diamond syndrome (2020)
  • Author(s): Takai Akari、Chiyonobu Tomohiro、Ueoka Ibuki、Tanaka Ryo、Tozawa Takenori、Yoshida Hideki、Morimoto Masafumi、Hosoi Hajime、Yamaguchi Masamitsu
  • Journal Title: Neuroscience Letters Volume: 739 Pages: 135449-135449
  • DOI: 10.1016/j.neulet.2020.135449
  • Peer Reviewed
• [Journal Article] Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster (2020)
  • Author(s): Takai Akari、Yamaguchi Masamitsu、Yoshida Hideki、Chiyonobu Tomohiro
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 17 Pages: 6442-6442
  • DOI: 10.3390/ijms21176442
  • Peer Reviewed / Open Access
• [Journal Article] Novel genetic link between the ATP-binding cassette subfamily A gene and hippo gene in Drosophila. (2020)
  • Author(s): Ueoka I, Takai A, Chiyohobu T, Yoshida H and Yamaguchi M.
  • Journal Title: Exp. Cell Res. Volume: 386 Issue: 2 Pages: 111733-111733
  • DOI: 10.1016/j.yexcr.2019.111733
  • Peer Reviewed / Int'l Joint Research
• [Presentation] ショウジョウバエモデルで明らかにしたALS，CMT，ASDへのHippo遺伝子の関与 (2020)
  • Author(s): 山口政光、東裕美子、櫛村由紀恵、上岡伊吹、高井あかり、吉田英樹、千代延友裕、徳田隆彦
  • Organizer: 第72回日本細胞生物学会
• [Presentation] ショウジョウバエを用いた神経発達症研究－リボソーム病への応用－ (2020)
  • Author(s): 高井あかり、千代延友裕、上岡伊吹、田中領、戸澤雄紀、吉田英樹、森本昌史、山口政光
  • Organizer: 第62回日本小児神経学会学術集会
• [Presentation] ショウジョウバエモデルを用いたリボソーム生合成異常による神経発達症の病態解析 (2019)
  • Author(s): 高井あかり、千代延友裕、上岡伊吹、山口瑞季、田中領、吉田英樹、山口政光
  • Organizer: 第42回日本分子生物学会年会