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Measuring RAN Peptide Toxicity in C. elegans
Published on: April 30, 2020
ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function
Tetsuro Murakami1, Seung-Pil Yang, Lin Xie
1Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
Abstract:
It is unclear whether mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis via a loss-of-function effect due to titrating FUS from the nucleus or a gain-of-function effect from cytoplasmic overabundance. To investigate this question, we generated a series of independent Caenorhabditis elegans lines expressing mutant or wild-type (WT) human FUS. We show that mutant FUS, but not WT-FUS, causes cytoplasmic mislocalization associated with progressive motor dysfunction and reduced lifespan. The severity of the mutant phenotype in C. elegans was directly correlated with the severity of the illness caused by the same mutation in humans, arguing that this model closely replicates key features of the human illness. Importantly, the mutant phenotype could not be rescued by overexpression of WT-FUS, even though WT-FUS had physiological intracellular localization, and was not recruited to the cytoplasmic mutant FUS aggregates. Our data suggest that FUS mutants cause neuronal dysfunction by a dominant gain-of-function effect related either to neurotoxic aggregates of mutant FUS in the cytoplasm or to dysfunction in its RNA-binding functions.
Insights
Mutations in fused in sarcoma (FUS) cause familial amyotrophic lateral sclerosis through a gain-of-function mechanism. Mutant FUS in the cytoplasm leads to motor deficits and shorter lifespan in a C. elegans model.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Familial amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease.
- The role of fused in sarcoma (FUS) mutations in ALS pathogenesis is debated, with theories including loss-of-function or gain-of-function mechanisms.
Purpose of the Study:
- To investigate whether fused in sarcoma (FUS) mutations cause familial ALS via loss-of-function or gain-of-function effects.
- To establish and validate a C. elegans model for studying FUS-linked ALS.
Main Methods:
- Generated Caenorhabditis elegans (C. elegans) lines expressing wild-type (WT) and mutant human FUS.
- Assessed motor function, lifespan, and FUS protein localization in generated C. elegans lines.
- Attempted to rescue mutant phenotypes through WT-FUS overexpression.
Main Results:
- Mutant FUS, unlike WT-FUS, caused cytoplasmic mislocalization, progressive motor dysfunction, and reduced lifespan in C. elegans.
- The severity of the observed mutant phenotype in C. elegans correlated with human ALS severity.
- Overexpression of WT-FUS did not rescue the mutant phenotype, indicating a dominant gain-of-function mechanism.
Conclusions:
- FUS mutations likely cause neuronal dysfunction in familial ALS through a dominant gain-of-function mechanism.
- This gain-of-function effect may stem from neurotoxic cytoplasmic aggregates of mutant FUS or impaired RNA-binding functions.
- The C. elegans model accurately recapitulates key features of human FUS-linked ALS.
