Fused in sarcoma (FUS) is an RNA-binding protein involved in pathogenesis of 
several neurodegenerative diseases. Aggregation of mislocalized FUS into 
non-amyloid inclusions is believed to be pivotal in the development of cell 
dysfunction, but the mechanism of their formation is unclear. Using transient 
expression of a panel of deletion and chimeric FUS variants in various cultured 
cells, we demonstrated that FUS accumulating in the cytoplasm nucleates a novel 
type of RNA granules, FUS granules (FGs), that are structurally similar but not 
identical to physiological RNA transport granules. Formation of FGs requires FUS 
N-terminal prion-like domain and the ability to bind specific RNAs. Clustering 
of FGs coupled with further recruitment of RNA and proteins produce larger 
structures, FUS aggregates (FAs), that resemble but are clearly distinct from 
stress granules. In conditions of attenuated transcription, FAs lose RNA and 
dissociate into RNA-free FUS complexes that become precursors of large 
aggresome-like structures. We propose a model of multistep FUS aggregation 
involving RNA-dependent and RNA-independent stages. This model can be 
extrapolated to formation of pathological inclusions in human FUSopathies.