Exploring the mechanisms of synaptic dysfunction related to loss-of-TDP-43 function in the pathogenesis of ALS/FTLD

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15707
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Nagoya University
• Principal Investigator: Li Jiayi 名古屋大学, 医学系研究科, 研究員 (40867420)
• Project Period (FY): 2022-02-01 – 2024-03-31
• Keywords: TDP-43 / ALS / synapse / neuron

Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, which affects both upper and lower motor neuron. Synaptic damage is observed in the early events, followed by neurodegeneration in ALS/FTLD. This study investigates the role of TDP-43 in synapse dysfunction during ALS progression. We created mice with conditional knockout of TDP-43 in neurons (TDP-43cKO). These mice exhibited reduced synapse numbers without obvious neuronal death and axonal damage. We isolated control and TDP-43 knockout neurons and analyzed their gene expression (RNAseq). This analysis revealed changes in genes associated with synapse function. Additionally, TDP-43cKO mice displayed memory deficits in novel object recognition test.

Free Research Field

内科学

Academic Significance and Societal Importance of the Research Achievements

ALS/FTLDでは、シナプス損傷が特徴的な病理学的変化である一方、神経細胞におけるTDP-43タンパク質とシナプス可塑性との関係は依然として不明である。我々の研究では、TDP-43タンパク質の喪失がマウスにおいてシナプス喪失と機能障害を引き起こすことを明らかにした。この発見は、ALS治療への新たな可能性を示唆している。