Challenges to the true molecular mechanism of TDP-43 proteinopathy from the aspect of cellular senescence.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K19442
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Niigata University
• Principal Investigator: Kato Taisuke 新潟大学, 脳研究所, 准教授 (30598496)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Keywords: TDP-43プロテイノパチー / 細胞質封入体 / 封入体シード / 細胞質核酸 / 細胞老化 / DNA損傷

Outline of Final Research Achievements

TDP-43 cytoplasmic inclusion in TDP-43-proteinopathy is suspected to be involved in neurodegeneration, but the mechanism remains unclear. In this study, we suspected the involvement of cellular senescence as a mechanism of TDP-43 cytoplasmic inclusion formation and explored the possibility that cytoplasmic leaky nucleic acids generated during cellular senescence may serve as a seed for inclusion body formation. The results of this study showed that the formation of TDP-43 inclusions is selective by cellular senescence induction methods and is particularly strongly induced by irradiation, that cytoplasmic double-stranded DNA molecules are highly co-localized with TDP-43 inclusion bodies, and that leaky DNA containing repetitive sequences may be involved.

Free Research Field

分子病態学

Academic Significance and Societal Importance of the Research Achievements

TDP-43がALS・FTLDなどの封入体構成成分であることが2006年に同定されて以降、未だにTDP-43細胞質封入体の形成機構が不明のままである。理由は、人為的発現操作なしでこれを再現できるモデルがなかったためである。申請者が解析に用いた本研究のモデルでは、外部からの遺伝子導入を介さずに、内在性因子の変動のみでTDP-43プロテイノパチーが再現されている。この現象のメカニズムの解明は、これまで世界中で用いられてきた古典的な人工モデル体型を再編する可能性があり、その制御はTDP-43プロテイノパチーの画期的な治療標的の提案に繋がることとなる。