Compound A alleviates astrocyte-mediated neuronal toxicity in amyotrophic lateral sclerosis models

초록

Fused in sarcoma (FUS) is DNA/RNA-binding protein that plays a role in various cellular functions, including transcription, RNA splicing, and DNA repair. Mutations in the FUS gene have been associated with several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, therapeutic options targeting FUS-mediated neurodegeneration remain extremely limited. Here, we identified compound A as a novel modulator of FUS-induced neurotoxicity. Treatment of compound A reduced mis-localization of FUS protein and activation of inflammatory response in FUS overexpressed astrocytes. Moreover, compound A ameliorated astrocytic FUS-induced neuronal toxicity and mitochondrial dysfunction. Furthermore, dietary administration of compound A significantly rescued lifespan shortening and locomotor deficits observed in a Drosophila model expressing FUS in glial cells. We also investigated another RNA-binding protein associated with ALS and FTD, TDP-43, and confirmed that compound A mitigated TDP-43-induced inflammatory responses and neurotoxicity in both cellular and Drosophila models of TDP-43 proteinopathy. Therefore, our findings suggest that compound A has the potential to be a novel therapeutic agent for ALS.