Fused in sarcoma (FUS) belongs to the group of RNA-binding proteins implicated 
as underlying factors in amyotrophic lateral sclerosis (ALS) and certain other 
neurodegenerative diseases. Multiple FUS gene mutations have been linked to 
hereditary forms, and aggregation of FUS protein is believed to play an 
important role in pathogenesis of these diseases. In cultured cells, FUS 
variants with disease-associated amino acid substitutions or short deletions 
affecting nuclear localization signal (NLS) and causing cytoplasmic 
mislocalization can be sequestered into stress granules (SGs). We demonstrated 
that disruption of motifs responsible for RNA recognition and binding not only 
prevents SG recruitment, but also dramatically increases the protein propensity 
to aggregate in the cell cytoplasm with formation of juxtanuclear structures 
displaying typical features of aggresomes. Functional RNA-binding domains from 
TAR DNA-binding protein of 43 kDa (TDP-43) fused to highly aggregation-prone 
C-terminally truncated FUS protein restored the ability to enter SGs and 
prevented aggregation of the chimeric protein. Truncated FUS was also able to 
trap endogenous FUS molecules in the cytoplasmic aggregates. Our data indicate 
that RNA binding and recruitment to SGs protect cytoplasmic FUS from 
aggregation, and loss of this protection may trigger its pathological 
aggregation in vivo.