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A novel model animal recapitulating ALS pathophysiology

Research Project

Project/Area Number 19K08006
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52020:Neurology-related
Research InstitutionNational Center of Neurology and Psychiatry

Principal Investigator

Takahashi Yuji  国立研究開発法人国立精神・神経医療研究センター, 病院, 部長 (00372392)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords筋萎縮性側索硬化症 / ErbB4 / コンディショナルノックアウトマウス / 運動神経細胞死 / コンディショナルノックアウト / 運動ニューロン / 神経細胞死 / モデルマウス
Outline of Research at the Start

ALSの原因遺伝子ERBB4の運動ニューロン(MN)特異的なノックアウトマウス(cKOマウス)を作製して、孤発性ALSの剖検組織に認められるErbB4の発現喪失がMN 変性を惹起するという仮説をin vivoで検証し、ALSの病態を再現するモデル動物を構築する。ChAT-CreERTマウスとErbb4flox/floxマウスの掛け合わせにより、タモキシフェン依存性cKOマウスを作製する。行動解析・神経生理学的解析・病理学的解析を行い、孤発性ALSのモデル動物としての妥当性を検証する。既知のALSの病態仮説における分子マーカーの挙動を解析するとともに、新規のMN変性関連分子の探索を行う。

Outline of Final Research Achievements

It is hypothesized that ErbB4 is essential for the survival of motor neurons and dysfunction of ErbB4 is a common pathology of ALS. To test the hypothesis in vivo, we generated tamoxiphen-dependent motor neuron-specific conditional knockout mice (cKO mice). In cKO mice, the appearance of clasping was observed 5 months after administration of tamoxiphen. Pathological analysis showed a 40% decrease in the number of spinal motor neurons 3 months after administration. The residual neurons maintained the stainability of ErbB4. We have obtained results supporting that ErbB4 is essential for the survival of mature spinal motor neurons and that cKO mice are model animals that recapitulate the pathophysiology of ALS.

Academic Significance and Societal Importance of the Research Achievements

本研究により、ErbB4が運動神経細胞の生存に必須であることが明らかになり、ErbB4の機能低下性変異・ErbB4発現低下が運動神経細胞死の直接の原因になり得ることが示された。ALSの新たな病態機構の解明という学術的意義と共に、根本治療の開発に向けた創薬シーズ候補分子の同定という社会的意義も有すると考えられる。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (3 results)

All 2019

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

  • [Journal Article] Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS2019

    • Author(s)
      Takahashi Yuji、Uchino Akiko、Shioya Ayako、Sano Terunori、Matsumoto Chihiro、Numata‐Uematsu Yurika、Nagano Seiichi、Araki Toshiyuki、Murayama Shigeo、Saito Yuko
    • Journal Title

      Neuropathology

      Volume: 39 Issue: 4 Pages: 268-278

    • DOI

      10.1111/neup.12558

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Exploring the frequency and clinical background of the “zebra sign” in amyotrophic lateral sclerosis and multiple system atrophy2019

    • Author(s)
      Atsuhiko Sugiyama, Noriko Sato, Yukio Kimura, Yoko Shigemoto, Fumio Suzuki, Emiko Morimoto, Yuji Takahashi, Hiroshi Matsuda, Satoshi Kuwabara
    • Journal Title

      Journal of the Neurological Sciences

      Volume: 401 Pages: 90-94

    • DOI

      10.1016/j.jns.2019.04.032

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Implication of rare variants in causative genes for Charcot-Marie-Tooth disease in patients clinically diagnosed as ALS2019

    • Author(s)
      Yuka Hama, Hidetoshi Date, Hiroyuki Ishiura, Jun Mitsui, Koichiro Doi, Jun Yoshimura, Shinichi Morishita, Shoji Tsuji, Hidehiro Mizusawa, Yuji Takahashi
    • Organizer
      30th International Symposium on ALS/MND
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-04-18   Modified: 2023-01-30  

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