Research for the pathogenesis and therapy of dysferlinopathy: Focusing on mechanisms of plasma membrane repair

• Project/Area Number: 18K15437
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Tohoku University
• Principal Investigator: Ono Hiroya 東北大学, 医学系研究科, 大学院非常勤講師 (90803578)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Discontinued (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 筋ジストロフィー / dysferlin / 細胞膜修復 / AMPK

Outline of Final Research Achievements

Mutations in dysferlin are responsible for a inherited muscular dystrophy known as dysferlinopathy. Using affinity purification method combined with liquid chromatography-tandem mass spectrometry, we found that AMP-activated protein kinase (AMPK)γ1 was bound to a specific region of dysferlin. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in human myotubes with dysferlinopathy and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.

Academic Significance and Societal Importance of the Research Achievements

国の指定難病である筋ジストロフィーは、筋肉の萎縮や筋力の低下といった障害を示す、進行性の難治性遺伝性疾患である。本研究で得られたAMPK複合体が損傷を受けた筋細胞膜の修復において重要な役割を担っているという新たな知見は、根治療法がいまだないdysferlinopathyひいては筋ジストロフィー全体の治療法の開発に結びつく可能性がある。

Research Products

• [Journal Article] The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype-phenotype relationship and a hotspot on the inner DysF domain (2020)
  • Author(s): Izumi Rumiko、Takahashi Toshiaki、Suzuki Naoki、Niihori Tetsuya、Ono Hiroya、Nakamura Naoko、Katada Shinichi、Kato Masaaki、Warita Hitoshi、Tateyama Maki、Aoki Yoko、Aoki Masashi
  • Journal Title: Human Mutation Volume: 41 Issue: 9 Pages: 1540-1554
  • DOI: 10.1002/humu.24036
  • Peer Reviewed
• [Journal Article] AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy (2020)
  • Author(s): Ono Hiroya、Suzuki Naoki、Kanno Shin-ichiro、Kawahara Genri、Izumi Rumiko、Takahashi Toshiaki、Kitajima Yasuo、Osana Shion、Nakamura Naoko、Akiyama Tetsuya、Ikeda Kensuke、Shijo Tomomi、Mitsuzawa Shio、Nagatomi Ryoichi、Araki Nobukazu、Yasui Akira、Warita Hitoshi、Hayashi Yukiko K.、Miyake Katsuya、Aoki Masashi
  • Journal Title: Molecular Therapy Volume: 28 Issue: 4 Pages: 1133-1153
  • DOI: 10.1016/j.ymthe.2020.02.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Dysferlinopathyに対する治療法の開発 (2020)
  • Author(s): 小野洋也, 鈴木直輝, 菅野新一郎, 川原玄理, 割田仁, 林由起子, 三宅克也, 青木正志
  • Organizer: 第38回日本神経治療学会学術集会
  • Invited
• [Presentation] ジスフェルリノパチーの治療法開発 (2020)
  • Author(s): 小野洋也, 髙橋俊明
  • Organizer: 第74回国立病院総合医学会
  • Invited
• [Presentation] 細胞膜修復機構に着目したdysferlin異常症の病態解明と治療法開発 (2018)
  • Author(s): 小野洋也、鈴木直輝、菅野新一郎、川原玄理、井泉瑠美子、髙橋俊明、北嶋康雄、長名シオン、秋山徹也、池田謙輔、四條友望、光澤志緒、割田 仁、永富良一、荒木伸一、安井 明、林 由起子、三宅克也、青木正志
  • Organizer: 日本筋学会第4回学術集会
• [Presentation] Novel binding partner of dysferlin is a potential therapeutic target for dysferlinopathy (2018)
  • Author(s): 小野洋也、鈴木直輝、菅野新一郎、川原玄理、井泉瑠美子、髙橋俊明、北嶋康雄、長名シオン、秋山徹也、池田謙輔、四條友望、光澤志緒、割田 仁、永富良一、荒木伸一、安井 明、林 由起子、三宅克也、青木正志
  • Organizer: 第59回日本神経学会学術大会
• [Remarks] 東北大学 プレスリリース：筋ジストロフィー(ジスフェルリン異常症)の新規治療標的を発見
  • URL: https://www.tohoku.ac.jp/japanese/2020/02/press20200225-04-AMPK.html
• [Remarks] 東北大学大学院医学系研究科・医学部 プレスリリース
  • URL: https://www.med.tohoku.ac.jp/news/4329.html
• [Remarks] 東北大学医学部神経内科 研究内容
  • URL: http://www.neurol.med.tohoku.ac.jp/group.html