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Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules.


ABSTRACT: Mutations in the RNA-binding protein FUS (fused in sarcoma) are linked to amyotrophic lateral sclerosis (ALS), but the mechanism by which these mutants cause motor neuron degeneration is not known. We report a novel ALS truncation mutant (R495X) that leads to a relatively severe ALS clinical phenotype compared with FUS missense mutations. Expression of R495X FUS, which abrogates a putative nuclear localization signal at the C-terminus of FUS, in HEK-293 cells and in the zebrafish spinal cord caused a striking cytoplasmic accumulation of the protein to a greater extent than that observed for recessive (H517Q) and dominant (R521G) missense mutants. Furthermore, in response to oxidative stress or heat shock conditions in cultures and in vivo, the ALS-linked FUS mutants, but not wild-type FUS, assembled into perinuclear stress granules in proportion to their cytoplasmic expression levels. These findings demonstrate a potential link between FUS mutations and cellular pathways involved in stress responses that may be relevant to altered motor neuron homeostasis in ALS.

SUBMITTER: Bosco DA 

PROVIDER: S-EPMC2981014 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules.

Bosco Daryl A DA   Lemay Nathan N   Ko Hae Kyung HK   Zhou Hongru H   Burke Chris C   Kwiatkowski Thomas J TJ   Sapp Peter P   McKenna-Yasek Diane D   Brown Robert H RH   Hayward Lawrence J LJ  

Human molecular genetics 20100810 21


Mutations in the RNA-binding protein FUS (fused in sarcoma) are linked to amyotrophic lateral sclerosis (ALS), but the mechanism by which these mutants cause motor neuron degeneration is not known. We report a novel ALS truncation mutant (R495X) that leads to a relatively severe ALS clinical phenotype compared with FUS missense mutations. Expression of R495X FUS, which abrogates a putative nuclear localization signal at the C-terminus of FUS, in HEK-293 cells and in the zebrafish spinal cord cau  ...[more]

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