Analysis of cell death mechanisms of ALS/FTD via phosphorylation of TDP-43

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07284
• 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: Tokyo Medical University
• Principal Investigator: Nawa Mikiro 東京医科大学, 医学部, 講師 (10398620)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: リン酸化 / TDP-43 / 筋萎縮性側索硬化症 / 前頭側頭型認知症

Outline of Final Research Achievements

We focused on and investigated the mechanism(s) of independently identified phosphorylation sites of TDP-43 using cell lines and animal models. We have shown that the novel phosphorylation sites of TDP-43 were essential for TDP-43-induced cell death. Next, we generated a series of substitution mutant mice in which phosphorylation sites were replaced by Ala, and the mutant mice showed no abnormalities in motor function. We also attempted to identify the kinase of the new phosphorylation sites by screening a kinase inhibitor library. Although we obtained several kinases that could inhibit TDP-43-induced cell death, we could not identify the kinase at the sites.

Free Research Field

神経細胞死

Academic Significance and Societal Importance of the Research Achievements

筋萎縮性側索硬化症や前頭側頭型認知症では細胞内にTDP-43がリン酸化された状態で蓄積することが知られているが、TDP-43のリン酸化と細胞死の直接的な関連性については不明な点が多かった。本研究では、TDP-43が誘導する細胞死に必須な新規リン酸化部位を同定した。また、TDP-43誘導性の細胞死を抑制する複数のキナーゼの同定にも成功し、TDP-43のリン酸化をターゲットとした筋萎縮性側索硬化症や前頭側頭型認知症の治療法につながる知見を得た。