Exploratiion of mechanisms for formation of aberrant stress granules and TDP-43 aggregates

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07291
• 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: Niigata University
• Principal Investigator: Kakihana Taichi 新潟大学, 医歯学系, 助教 (60746907)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 筋萎縮性側索硬化症 / ストレス顆粒

Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by dysfunction and cell death of motor neurons in the brainstem and spinal cord and the resulting motor deficits. TDP-43 is the causative protein in familial and arcuate ALS; in ALS motor neurons, ubiquitinated TDP-43 forms aggregates in the cytoplasm, which induce neuronal dysfunction and cell death, resulting in ALS. Stress granules are non-membrane organelles that form transiently under stress. Stress granules have recently been shown to be involved in the formation of ubiquitinated TDP-43 aggregates. We have elucidated the quality control mechanism of stress granule formation and the mechanism of TDP-43 aggregate formation in ALS(Kakihana, iScience, 2021; Takahashi, Mol Cell Biol, 2022; Sango, J Biol Chem, 2022), and have opened up a new research area.

Free Research Field

ウイルス学

Academic Significance and Societal Importance of the Research Achievements

ストレス顆粒の形成異常が、神経変性疾患やがん、糖尿病などの原因として示唆されている。代表者らは、ストレス顆粒の形成異常を引き起こす複数の細胞内経路を同定することができた。同定された細胞内経路は、ALSやパーキンソン病などの原因となるタンパク質やストレス因子の毒性を緩和することが判明した。これらの研究成果を発展させることで、新たな治療、創薬標的を創出することが期待できる。