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

作者：Bosco Daryl A^*; Lemay Nathan; Ko Hae Kyung; Zhou Hongru; Burke Chris; Kwiatkowski Thomas J Jr; Sapp Peter; McKenna Yasek Diane; Brown Robert H Jr; Hayward Lawrence J

来源：Human Molecular Genetics, 2010, 19(21): 4160-4175.

DOI：10.1093/hmg/ddq335

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.

• 出版日期2010-11-1