Premium
Nuclear transport impairment of amyotrophic lateral sclerosis‐linked mutations in FUS/TLS
Author(s) -
Ito Daisuke,
Seki Morinobu,
Tsunoda Yoshiko,
Uchiyama Hidemi,
Suzuki Norihiro
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22246
Subject(s) - frontotemporal lobar degeneration , amyotrophic lateral sclerosis , biology , mutant , stress granule , microbiology and biotechnology , mutation , neurodegeneration , nuclear transport , cytoplasm , nuclear export signal , rna binding protein , frontotemporal dementia , cell nucleus , rna , genetics , gene , messenger rna , pathology , medicine , dementia , disease , translation (biology)
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. Ann Neurol 2010