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Elucidation of the Molecular Basis of Axonal Branching Abnormalities in Amyotrophic Lateral Sclerosis Models

Research Project

Project/Area Number 21K07411
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52020:Neurology-related
Research InstitutionTohoku University

Principal Investigator

Suzuki Naoki  東北大学, 大学病院, 助教 (70451599)

Co-Investigator(Kenkyū-buntansha) 割田 仁  東北大学, 大学病院, 助教 (30400245)
青木 正志  東北大学, 医学系研究科, 教授 (70302148)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
KeywordsALS / 筋萎縮性側索硬化症
Outline of Research at the Start

筋萎縮性側索硬化症 (ALS) は運動ニューロンが系統的・選択的に障害される難病である。申請者らは運動ニューロンの特徴的な構造であり、ヒトで1mにも及ぶ長い軸索がALS病態の初期から障害されていることに着目し、独自に開発したマイクロ流体デバイスを用いて培養下で軸索構造を再現し、病態の鍵となる分子を同定してきた。ALS変異iPS細胞由来運動ニューロンにおける軸索形態異常がALSにおける神経変性に直結するかは不明確だった。本研究では、ALS共通病態としての軸索分岐異常の分子基盤は何か、軸索病態を改善することが神経変性抑制につながるのか、という二つの未解決課題に取り組む。

Outline of Final Research Achievements

In this study, we optimized a differentiation culture protocol for autonomic and sensory neurons and confirmed axon bundle formation within microfluidic devices. Utilizing microfluidic devices, we conducted Axon-seq comparative analysis by separating cell bodies and axons to identify 16 genes associated with minimal impairment in motor neurons in the pathogenesis of ALS. Additionally, as an in vivo experimental model, we established FUS mutation knock-in mice and established stable colonies through backcrossing. By analyzing the neuromuscular junctions using proteomics, we were able to identify novel disease-related proteins. By accumulating insights at both cellular and organismal levels, we aim to identify molecules that could serve as novel therapeutic targets for ALS.

Academic Significance and Societal Importance of the Research Achievements

これまでのALS病態研究は神経細胞体に注目したものが多く、ニューロンの特徴的な構造である軸索病態に真正面から取り組んだ研究はほとんどなかった。本研究はiPS細胞活用における問題点である発生と老化病態の違いにも留意しつつ、マウスやヒト剖検脳も駆使し、形態と機能の相関を検討し、軸索における恒常性維持機構の各機序の相互作用についても解析を進める。ALSの病態を軸索という構造・機能から捉えなおすことで、新たな治療法開発へとつなげることが期待される。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (9 results)

All 2024 2023 2022 2021

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (2 results) (of which Invited: 1 results)

  • [Journal Article] Nationwide survey of patients with multisystem proteinopathy in Japan2024

    • Author(s)
      Yamashita Satoshi、Takahashi Yuji、Hashimoto Jun、Murakami Ayuka、Nakamura Ryoichi、Katsuno Masahisa、Izumi Rumiko、Suzuki Naoki、Warita Hitoshi、Aoki Masashi、the Japan MSP Study Group
    • Journal Title

      Annals of Clinical and Translational Neurology

      Volume: - Issue: 4 Pages: 938-945

    • DOI

      10.1002/acn3.52011

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery2023

    • Author(s)
      Morimoto Satoru、Takahashi Shinichi、Ito Daisuke et al.
    • Journal Title

      Cell Stem Cell

      Volume: 30 Issue: 6 Pages: 766-780.e9

    • DOI

      10.1016/j.stem.2023.04.017

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits2023

    • Author(s)
      Li Dan、Johmura Yoshikazu、Morimoto Satoru et al.
    • Journal Title

      Nature Aging

      Volume: 3 Issue: 8 Pages: 1001-1019

    • DOI

      10.1038/s43587-023-00464-4

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nuclear pore pathology underlying multisystem proteinopathy type 3‐related inclusion body myopathy2023

    • Author(s)
      Izumi Rumiko、Ikeda Kensuke、Niihori Tetsuya、Suzuki Naoki、Shirota Matsuyuki、Funayama Ryo、Nakayama Keiko、Warita Hitoshi、Tateyama Maki、Aoki Yoko、Aoki Masashi
    • Journal Title

      Annals of Clinical and Translational Neurology

      Volume: 11 Issue: 3 Pages: 577-592

    • DOI

      10.1002/acn3.51977

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Phase II/III Study of Aceneuramic Acid Administration for GNE Myopathy in Japan2023

    • Author(s)
      Suzuki Naoki、Mori-Yoshimura Madoka、Katsuno Masahisa、Takahashi Masanori P.、Yamashita Satoshi、Oya Yasushi、Hashizume Atsushi、Yamada Shinichiro、Nakamori Masayuki、Izumi Rumiko、Kato Masaaki、Warita Hitoshi、Tateyama Maki、Kuroda Hiroshi、Asada Ryuta、Yamaguchi Takuhiro、Nishino Ichizo、Aoki Masashi
    • Journal Title

      Journal of Neuromuscular Diseases

      Volume: - Issue: 4 Pages: 1-12

    • DOI

      10.3233/jnd-230029

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy2022

    • Author(s)
      Suzuki Naoki、Nishiyama Ayumi、Warita Hitoshi、Aoki Masashi
    • Journal Title

      Journal of Human Genetics

      Volume: 68 Issue: 3 Pages: 131-152

    • DOI

      10.1038/s10038-022-01055-8

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations2021

    • Author(s)
      Mitsuzawa S, Suzuki N, Akiyama T, Ishikawa M, Sone T, Kawada J, Funayama R, Shirota M, Mitsuhashi H, Morimoto S, Ikeda K, Shijo T, Ohno A, Nakamura N, Ono H, Ono R, Osana S, Nakagawa T, Nishiyama A, Izumi R, Kaneda S, Ikeuchi Y, Nakayama K, Fujii T, Warita H, Okano H, Aoki M.
    • Journal Title

      Stem Cell Reports

      Volume: 16 Issue: 6 Pages: 1527-1541

    • DOI

      10.1016/j.stemcr.2021.04.021

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Advanced Medicine for ALS2023

    • Author(s)
      鈴木直輝
    • Organizer
      第64回 日本神経学会 学術大会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Molecular mechanism of motor neuron disease unravelled: achievements from the interdisciplinary collaboration2023

    • Author(s)
      鈴木直輝
    • Organizer
      第46回日本神経科学会
    • Related Report
      2023 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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