Elucidation of physiological and pathological roles of TDP-43 through autophagic machinery

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07364
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: The University of Tokyo
• Principal Investigator: Hashimoto Tadafumi 東京大学, 大学院医学系研究科(医学部), 特任准教授 (30334337)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: TDP-43 / FUS / 筋萎縮性側索硬化症 / 前頭側頭葉変性症

Outline of Final Research Achievements

Aberrant accumulation of TDP-43 or FUS in the affected motor neurons of patients with amyotrophic lateral sclerosis (ALS) is a pathological feature of ALS, however the molecular mechanisms whereby TDP-43 induced the neurodegeneration remained unclear. Here, we found that ULK1 mRNA was interacted with TDP-43, and knockdown of TDP-43 reduced the level of protein of ULK1. Knockdown of TDP-43 also reduced the level of LC3-II, indicating that TDP-43 has an important role in the regulation of autophagy. Moreover, ULK1 deficient mice exhibited severer motor dysfunction in the AAV9-TDP-43 model. These data suggest that autophagy regulates neurodegeneration induced by TDP-43.

Free Research Field

病態生化学

Academic Significance and Societal Importance of the Research Achievements

脊髄前角の運動ニューロンが変性脱落することにより、重篤な筋萎縮を引き起こす神経難病である筋萎縮性側索硬化症において、どのような機序で運動乳論が神経変性を起こすのか不明であった。本研究ではタンパク質の品質管理に重要な機構であるオートファジーが、TDP-43の神経毒性に関与することを明らかにした。この結果はこれまで根本治療薬のなかった筋萎縮性側索硬化症に、新たな治療標的を提供するものである。