Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, have been 
associated with familial amyotrophic lateral sclerosis (fALS), which is a fatal 
neurodegenerative disease that causes progressive muscular weakness and has 
overlapping clinical and pathologic characteristics with frontotemporal lobar 
degeneration. However, the role of autophagy in regulation of FUS-positive 
stress granules (SGs) and aggregates remains unclear. We found that the 
ALS-linked FUS(R521C) mutation causes accumulation of FUS-positive SGs under 
oxidative stress, leading to a disruption in the release of FUS from SGs in 
cultured neurons. Autophagy controls the quality of proteins or organelles; 
therefore, we checked whether autophagy regulates FUS(R521C)-positive SGs. 
Interestingly, FUS(R521C)-positive SGs were colocalized to RFP-LC3-positive 
autophagosomes. Furthermore, FUS-positive SGs accumulated in atg5(-/-) mouse 
embryonic fibroblasts (MEFs) and in autophagy-deficient neurons. However, 
FUS(R521C) expression did not significantly impair autophagic degradation. 
Moreover, autophagy activation with rapamycin reduced the accumulation of 
FUS-positive SGs in an autophagy-dependent manner. Rapamycin further reduced 
neurite fragmentation and cell death in neurons expressing mutant FUS under 
oxidative stress. Overall, we provide a novel pathogenic mechanism of ALS 
associated with a FUS mutation under oxidative stress, as well as therapeutic 
insight regarding FUS pathology associated with excessive SGs.