Development of Therapeutic Strategies for Amyotrophic Lateral Sclerosis (ALS) through Modulation of RNA-Binding Protein Levels

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K07016
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Aichi Gakuin University (2023); Nagoya City University (2020-2022)
• Principal Investigator: TSUIJI Hitomi 愛知学院大学, 薬学部, 教授 (40455358)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: ALS

Outline of Final Research Achievements

Mutations in the RNA-binding protein FUS are observed in approximately 5% of familial ALS patients. In this study, we focused on FUS and Ataxin-2, aiming to elucidate the mechanisms of motor neuron degeneration mediated by these proteins. We generated ALS model mice expressing mutant FUS. The mutant FUS transgenic mice exhibited ALS-like symptoms such as weight loss, decreased survival rate, and neurological abnormalities. By crossing these mice with FUS knockout mice or Ataxin-2 knockout mice, we generated mice with a reduced level of nuclear FUS protein or Ataxin-2 protein. We observed an improvement in neurological abnormalities, as indicated by clasping behavior, in mice with a reduced level of nuclear FUS protein. While motor function deteriorated, there was an improvement in weight and survival rate of mice with a reduced level of Ataxin-2. These findings suggest that reducing the levels of FUS or Ataxin-2 may ameliorate ALS pathology in mutant FUS transgenic mice.

Free Research Field

神経病態学

Academic Significance and Societal Importance of the Research Achievements

筋萎縮性側索硬化症ALSは根治療法がない神経難病である。本研究により、FUSやAtaxin-2タンパク質量を減少させることがALS病態を改善する可能性が示唆された。