GSBS Student Publications

Title

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

Student Author(s)

Hae Kyung Ko

GSBS Program

Cell Biology

Publication Date

2010-11-01

UMMS Affiliation

Department of Neurology

Document Type

Article

Disciplines

Molecular Genetics | Nervous System Diseases | Neurology | Neuroscience and Neurobiology

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.

DOI of Published Version

10.1093/hmg/ddq335

Source

Hum Mol Genet. 2010 Nov 1;19(21):4160-75. doi: 10.1093/hmg/ddq335. Epub 2010 Aug 10. Link to article on publisher's site

Journal/Book/Conference Title

Human molecular genetics

Related Resources

Link to Article in PubMed

PubMed ID

20699327

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