Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules.
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.
Bosco
Daryl A
DA
Department of Neurology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA. daryl.bosco@umassmed.edu
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
D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D018384:Oxidative Stress; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015027:Zebrafish
D034702:RNA-Binding Protein FUS; D049452:Green Fluorescent Proteins