ArticleHuman molecular genetics2012
ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 121 citations in OpenAlex.
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- The prion-like effect and prion-like protein targeting strategy in amyotrophic lateral sclerosis.Heliyon · 2024Review
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- Towards Understanding Neurodegenerative Diseases: Insights fromInternational journal of molecular sciences · 2023Review
- Pathological insights from amyotrophic lateral sclerosis animal models: comparisons, limitations, and challenges.Translational neurodegeneration · 2023Review
- G3BP1-dependent mechanism suppressing protein aggregation in Huntington's models and its demise upon stress granule assembly.Human molecular genetics · 2023Article
- Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes.Nature aging · 2023Article
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- Simple models to understand complex disease: 10 years of progress fromFrontiers in neuroscience · 2023Review
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- Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives.International journal of molecular sciences · 2021Review
- An autoregulation loop in fust-1 for circular RNA regulation in Caenorhabditis elegans.Genetics · 2021Article
- Caenorhabditis elegans for rare disease modeling and drug discovery: strategies and strengths.Disease models & mechanisms · 2021Review
- Evidence of synergism among three genetic variants in a patient with LMNA-related lipodystrophy and amyotrophic lateral sclerosis leading to a remarkable nuclear phenotype.Molecular and cellular biochemistry · 2021Article
- Systemic regulation of mitochondria by germline proteostasis prevents protein aggregation in the soma ofScience advances · 2021Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 4 institutions in 3 countries.
Funding
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.
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Registered trials
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