Natural compound A: a novel therapeutic agent for ALS/FTD

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, treatments for FUS-mediated neurodegeneration are 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 alleviates astrocytic FUS-induced neuronal toxicity and mitochondrial dysfunction. We also found that a shortened lifespan and motility defects in glial FUS expressing Drosophila are significantly mitigated by dietary treatment with compound A. TDP-43 is another RNA-binding protein associated with ALS and FTD. Thus, we investigate the effect of compound A on TDP-43 toxicity. We also found that compound A attenuates TDP-43-induced inflammatory response and neuronal toxicity in fly and cell TDP-43 proteinopathy model. Therefore, our findings suggest that compound A has the potential to be a novel therapeutic agent for ALS.