Compound A attenuates non-cell-autonomous neurotoxicity in multiple preclinical ALS/FTD models

초록

Fused in sarcoma (FUS) is a DNA/RNA-binding protein that is implicated in various cellular processes, including transcription, RNA splicing, and DNA repair. Mutations in the FUS gene have been linked to several neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, treatment strategies for FUS-mediated neurodegeneration remain extremely limited. Here, we identified compound A as a novel modulator of FUS-induced neurotoxicity. Treatment with compound A decreased the cytoplasmic mislocalization of FUS protein and suppressed the activation of inflammatory responses in astrocytes overexpressing FUS. Moreover, compound A ameliorated astrocytic FUS-induced neuronal toxicity and mitochondrial dysfunction. We further demonstrated that the shortened lifespan and impaired locomotor activity observed in Drosophila expressing glial FUS were significantly rescued by dietary administration of compound A. TDP-43, another RNA-binding protein associated with ALS and FTD, was also investigated. We found that compound A attenuated TDP-43-induced inflammatory responses and neuronal toxicity in both cellular and Drosophila models of TDP-43 proteinopathy. Taken together, these findings suggest that compound A has promise as a potential therapeutic agent for ALS.