ArticleeLife2019
Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis.
Article in eLife, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 90 citations in OpenAlex.
- RNArchitects: how hnRNPs shape neuronal landscapes.Brain : a journal of neurology · 2026Review
- Human FUS is toxic via association with RNA polymerase II in Drosophila.Cell death & disease · 2026Article
- Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.Nature neuroscience · 2026Article
- Article
- Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis.Molecular neurobiology · 2025Review
- M6A-dependent RNA condensation underlies FUS autoregulation and can be harnessed for ALS therapy development.Science advances · 2025Article
- Maintenance of neuronal TDP-43 expression requires axonal lysosome transport.bioRxiv : the preprint server for biology · 2025Article
- RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.Molecular neurodegeneration · 2025Review
- Cytoplasmic accumulation of a splice variant of hnRNPA2/B1 contributes to FUS-associated toxicity in a mouse model of ALS.Cell death & disease · 2025Article
- The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).Autophagy reports · 2025Review
- Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS.Nature communications · 2024Article
- Changes in vocal fold gene expression and histology after injection augmentation in a recurrent laryngeal nerve injury model.The Journal of laryngology and otology · 2024Article
- Review
- Fused in sarcoma regulates glutamate signaling and oxidative stress response.Free radical biology & medicine · 2024Article
- FUS-dependent microRNA deregulations identify TRIB2 as a druggable target for ALS motor neurons.iScience · 2023Article
- Pathological insights from amyotrophic lateral sclerosis animal models: comparisons, limitations, and challenges.Translational neurodegeneration · 2023Review
- Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration.The Journal of clinical investigation · 2023Article
- Cytoplasmic aggregation of mutant FUS causes multistep RNA splicing perturbations in the course of motor neuron pathology.Nucleic acids research · 2023Article
- Identification of mitophagy-related biomarkers and immune infiltration in major depressive disorder.BMC genomics · 2023Article
- FUS Alters circRNA Metabolism in Human Motor Neurons Carrying the ALS-Linked P525L Mutation.International journal of molecular sciences · 2023Article
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Authors and funding
28 authors at 4 institutions in 4 countries.
Funding
Abstract
Mutations in coding and non-coding regions of FUS cause amyotrophic lateral sclerosis (ALS). The latter mutations may exert toxicity by increasing FUS accumulation. We show here that broad expression within the nervous system of wild-type or either of two ALS-linked mutants of human FUS in mice produces progressive motor phenotypes accompanied by characteristic ALS-like pathology. FUS levels are autoregulated by a mechanism in which human FUS downregulates endogenous FUS at mRNA and protein levels. Increasing wild-type human FUS expression achieved by saturating this autoregulatory mechanism produces a rapidly progressive phenotype and dose-dependent lethality. Transcriptome analysis reveals mis-regulation of genes that are largely not observed upon FUS reduction. Likely mechanisms for FUS neurotoxicity include autophagy inhibition and defective RNA metabolism. Thus, our results reveal that overriding FUS autoregulation will trigger gain-of-function toxicity via altered autophagy-lysosome pathway and RNA metabolism function, highlighting a role for protein and RNA dyshomeostasis in FUS-mediated toxicity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.