Mechanisms of motor neuron homeostasis and ALS therapeutic strategies focusing on TDP-43 dysfunction.

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K15904
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Hasegawa Minami 東京慈恵会医科大学, 医学部, 助教 (00778764)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ALS / TDP-43 / スプライスバリアント

Outline of Final Research Achievements

In this study, we examined whether TDPsv, which exhibits dominant-negative activity against full-length TDP-43, is neurotoxic, and the mechanism of its dominant-negative activity. Our results indicate that the dominant-negative activity of TDPsv is due to its competitive inhibition of full-length TDP-43 homodimer formation. We also found that TDPsv is neurotoxic in iPS cell-derived neurons. Thus, it is suggested that if levels of TDPsv, whose expression is normally suppressed, are exceed a threshold, TDP-43 function may deviate from optimal range for over a long period of time, ultimately leading to the ALS-induced neurodegeneration over a long period of time.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

ALSの9割を占める孤発性ALSにおいてTDP-43スプライシング機能の低下が見られていること、遺伝子変異の有無に関わらずほとんどのALS死後病理においてTDP-43の特徴的所見を示すことから、ALSでは原因に関わらず最終的にTDP-43の機能異常に収束することが示唆される。本研究成果はALSにおいて重要なTDP-43の機能維持メカニズムの解明に繋がる新たな知見を提供することができると考える。本知見をもとに今後はTDP-43の機能を是正するALS治療戦略や、TDP-43の機能をモニタリングしALS診断を可能とするバイオマーカーの開発等に繋がることが期待される。