Establishment of common mechanism and therapeutic base for amyotrophic lateral sclerosis based on a novel causative gene

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09689
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: National 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)
• Research Collaborator: Nagano Seiichi ; Date Hidetoshi ; Saito Yuko ; Matsumoto Chihiro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 筋萎縮性側索硬化症 / 運動神経細胞死 / ErbB4 / 軸索伸長 / コンディショナルノックアウトマウス / モデル動物

Outline of Final Research Achievements

The purpose of this study is to elucidate the mechanism by which dysfunction of the novel causative gene product ErbB4 of amyotrophic lateral sclerosis leads to spinal motor neuron death. In Neuro2A cells, subcellular mislocalization of mutant ErbB4 and resultant decreased cell viability were confirmed. In mouse cerebral cortex neuron-derived primary culture cells, it was revealed that the axonal elongating effect of the nuclear translocation isoform was abolished in the mutant form. A tamoxifen-dependent motor neuron specific ErbB4 conditional knockout mouse was created, and it was confirmed in vivo that loss of expression of ErbB4 leads to motor dysfunction and spinal motor neuron death. Thus, research progressed as intended within the designated period.

Free Research Field

神経内科学、分子遺伝学、分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究によりErbB4の機能喪失というALSの新たな病態メカニズムが明らかになった。さらに、孤発性ALSの病態を反映した新たな動物モデルの作成に成功した。本動物モデルは孤発性ALSの病態解明に活用可能であり、変性過程を前向きに追跡することが可能な有用なモデルである。一方、ErbB4は受容体型チロシンリン酸化酵素であり、創薬ターゲットとしても有用な分子である。ALSの病態抑制治療を目指した創薬シーズの開発に向けて重要な知見が得られたと考えられる。