PUBLICATION
Mutant FUS Proteins that Cause Amyotrophic Lateral Sclerosis Incorporate into Stress Granules
- Authors
- Bosco, D.A., Lemay, N., Ko, H.K., Zhou, H., Burke, C., Kwiatkowski, T.J. Jr, Sapp, P., McKenna-Yasek, D., Brown, R.H. Jr, and Hayward, L.J.
- ID
- ZDB-PUB-100820-1
- Date
- 2010
- Source
- Human molecular genetics 19(21): 4160-4175 (Journal)
- Registered Authors
- Hayward, Lawrence
- Keywords
- none
- MeSH Terms
-
- Adult
- Amyotrophic Lateral Sclerosis/genetics*
- Animals
- Cell Line
- Cytoplasm/metabolism
- Female
- Green Fluorescent Proteins/genetics
- Humans
- Male
- Middle Aged
- Mutation, Missense
- Oxidative Stress
- RNA-Binding Protein FUS/genetics
- RNA-Binding Protein FUS/metabolism
- RNA-Binding Protein FUS/physiology*
- Zebrafish
- PubMed
- 20699327 Full text @ Hum. Mol. Genet.
Citation
Bosco, D.A., Lemay, N., Ko, H.K., Zhou, H., Burke, C., Kwiatkowski, T.J. Jr, Sapp, P., McKenna-Yasek, D., Brown, R.H. Jr, and Hayward, L.J. (2010) Mutant FUS Proteins that Cause Amyotrophic Lateral Sclerosis Incorporate into Stress Granules. Human molecular genetics. 19(21):4160-4175.
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 causes a relatively severe ALS clinical phenotype compared to 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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping