OBJECTIVE: The fused in sarcoma/translated in liposarcoma (FUS/TLS) protein was 
recently identified as a cause of familial amyotrophic lateral sclerosis (ALS), 
as well as a major component of the inclusion bodies found in subtypes of 
frontotemporal lobar degeneration (FTLD). These diseases now are collectively 
known as the novel clinical spectrum, FUS proteinopathy. ALS-linked mutations of 
FUS are clustered in the C-terminal region; however, the molecular properties of 
mutant FUS remain unclear. To gain insight into the pathogenesis of FUS 
proteinopathy, we examined the biochemical and cellular characteristics of 
mutant FUS in expressing cells.
METHODS AND RESULTS: Expression of ALS-linked FUS mutations resulted in their 
assembly into cytoplasmic stress granules (SGs), cellular structures that 
package mRNA and RNA-binding proteins during cell stress. A deletion mutant 
series revealed that the C-terminal region in FUS is critical for nuclear 
retention via Ran guanosine triphosphatase-dependent transport machinery. A 
parallel study of subcellular distribution revealed that ALS-linked mutants 
additively disturb the function of the C-terminus for nuclear traffic, resulting 
in cytoplasmic accumulation and the formation of SGs.
INTERPRETATION: This study demonstrates that mutant FUS, which is missing the 
nuclear traffic activity of the C-terminus, is dislocated to cytoplasm and 
assembled into SGs, indicating that disruption of translational regulation and 
metabolism of mRNA via inappropriate/excessive SGs may be crucial for FUS 
proteinopathies. Our findings provide new biological and pathological insights 
into the FUS protein that should help our understanding of the pathogenesis of 
ALS/FTLD.