Journal
HUMAN MOLECULAR GENETICS
Volume 19, Issue 21, Pages 4160-4175Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddq335
Keywords
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Funding
- ALS Association
- ALS Therapy Alliance
- National Institute for Neurological Disease and Stroke [1RC2NS070342, 1RC1NS068391, R01NS050557, U01NS05225]
- Angel Fund
- ALS
- Pierre L. de Bourgknecht ALS Research Foundation
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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.
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