Disruption of the mitochondria-associated membranes as a general pathomechanism in amyotrophic lateral sclerosis

2021 Fiscal Year Final Research Report

• Project/Area Number: 17H04986
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Nagoya University
• Principal Investigator: Watanabe Seiji 名古屋大学, 環境医学研究所, 助教 (70633577)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: 小胞体・ミトコンドリア膜間領域 / σ1受容体 / TANK結合キナーゼ1 / 筋萎縮性側索硬化症

Outline of Final Research Achievements

In this study, we tested the hypothesis that disruption of the membrane contact region between the endoplasmic reticulum and mitochondria (ER-mitochondrial intermembrane region; MAM) is a general pathogenesis in amyotrophic lateral sclerosis (ALS). We generated a novel reporter molecule named MAMtracker and demonstrated that the MAM is disrupted by various ALS-causing genes. Furthermore, we found that MAM disruption significantly reduces the activity of TANK-binding kinase 1 (TBK1), which is also the causative gene product of ALS, and that this is due to impaired stress-dependent MAM-specific ubiquitination. This study will provide the basis for future development of MAM-targeted ALS therapies.

Free Research Field

病態神経科学

Academic Significance and Societal Importance of the Research Achievements

我々はこれまでにMAMの破綻がSOD1またはσ1受容体の変異に伴うALSで共通した病態であることを明らかにした。本研究では、これら以外のALS原因遺伝子によってもMAMの破綻が引き起こされることを明らかにし、MAMの破綻がALSにおいて普遍的な病態であることが示唆された。特にTBK1活性化へのMAMの関与はMAMの新規機能として興味深く、今後のALS治療における重要な標的機序となることが期待される。