Drug T alleviates TDP-43 toxicity by inhibition of eIF2a phosphorylation

초록

Aggregates of the RNA-binding protein TDP-43 are a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), with disease-associated mutations increasing TDP-43 mitochondrial localization. This study investigates the neuroprotective effects of Drug T on TDP-43-induced cytotoxicity. In SH-SY5Y cells, Drug T treatment significantly reduced TDP-43-induced cytotoxicity, evidenced by decreased expression of cytoplasmic TDP-43, p-eIF2a (Ser51), and P62/SQSTM1 levels, and reduced cell death as observed in real-time cell viability assays and flow cytometry. Drug T did not alter the overall TDP-43 protein level but reduced its cytoplasmic mislocalization, suggesting a modulation of TDP-43 localization. Additionally, Drug T alleviated mitochondrial dysfunction caused by TDP-43 overexpression, restoring key mitochondrial respiration parameters such as basal and maximal respiration rates and ATP production. In a Drosophila model of TDP-43 proteinopathies, Drug T treatment significantly improved lifespan and motor functions, indicating its potential as a therapeutic intervention for TDP-43-linked neurodegenerative diseases. These findings suggest that Drug T exerts its neuroprotective effects by alleviating TDP-43-induced cellular and mitochondrial stress, reducing cytoplasmic TDP-43, and enhancing cell survival in vitro and in vivo. Thus, Drug T shows promise as a therapeutic agent for treating TDP-43-associated neurodegenerative disorders, including ALS and FTD.