Molecular dynamics of TDP-43 and oxidized RNA in ALS pathogenesis

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K07439
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: LU JUN 国立研究開発法人国立国際医療研究センター, その他部局等, 研究員 (40507498)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 筋萎縮性側索硬化症(ALS) / 加齢因子 / 酸化ストレス

Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the accumulation of protein aggregates in motor neurons. Like TDP-43, FUS (fused in sarcoma), an ALS-associated RNA-binding protein, was also shown to play an important role in interacting with guanine quadruplexes. However, while many familial and sporadic ALS mutations are presumed to have reduced interaction with guanine quadruplex RNA, it is unclear why symptoms do not occur at a young age and the risk increases with age not yet. Therefore, we conducted next-generation sequencing (NGS) of primary cultured neurons subjected to oxidative stress. There were 191 genes whose gene expression significantly changed by a factor of two or more due to this aging factor (oxidative stress). It is necessary to further analyze the relationship between these genes and various factors (TDP-43, FUS, etc.) that have been involved in the development of ALS.

Free Research Field

基礎研究

Academic Significance and Societal Importance of the Research Achievements

筋萎縮性側索硬化症(ALS)の発症機序を解明するため、ALS関連RNA結合タンパク質の一つ、FUS（fused in sarcoma）がグアニン四重鎖との相互作用に重要な役割を示された。2021年11月に本研究の成果として発表した。しかし、家族性及び孤発生ALS変異の多くはグアニン四重鎖RNAとの相互作用が低下していると推定される一方で、何故若年では発症に至らず、加齢によりリスクが高まるかは解っていない。そこで、加齢因子（酸化ストレス）によって発現が2倍以上有意に変動する遺伝子191個判明できた。全体を理解するには更なる解析する必要。