ArticleThe Journal of clinical investigation2014
ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 183 papers.
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Who cites it
183 citing papers in PubMed, 267 citations in OpenAlex.
- Autoimmune processes and production of catalytically active antibodies-abzymes in prone to amyotrophic lateral sclerosis FUS(1-359) mice.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- Review
- A mutation in the nuclear speckle and splicing factor SRRM2 is associated with multisystem proteinopathy and causes dysregulation of synapse-associated genes.RNA (New York, N.Y.) · 2026Article
- Protein-First, but Not Protein-Only: Rethinking Neurodegenerative Diseases Through Transgenic Mouse Models.Neurology international · 2026Article
- Human iPSC-Derived Spinal Neurons Carrying the ALS FUS (P525L) Mutation Exhibit Lower Response to Inhibitory Neurotransmitters.Cellular and molecular neurobiology · 2026Article
- BDNF insufficiency exacerbates ALS progression.Cell reports. Medicine · 2026Article
- MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis.Brain : a journal of neurology · 2026Article
- A role for the cholinergic neuron circadian clock in RNA metabolism and mediating neurodegeneration.Life science alliance · 2026Article
- Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains.Molecular cell · 2026Article
- Exercise alone or combined with functional foods in aging and age-related diseases: targeting DNA damage, repair pathways, and genome integrity.Frontiers in aging neuroscience · 2026Review
- Review
- Biomolecular condensates: molecular structure, biological functions, diseases, and therapeutic targets.Molecular biomedicine · 2025Review
- RNA Binding Mechanism of the FUS Zinc Finger in Concert with Its Flanking Intrinsically Disordered Region.Journal of chemical information and modeling · 2025Article
- Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses.Cells · 2025Review
- Review
- Multiple lines of evidence for disruption of nuclear lamina and nucleoporins in FUS amyotrophic lateral sclerosis.Brain : a journal of neurology · 2024Article
- Engineered NLS-chimera downregulates expression of aggregation-prone endogenous FUS.Nature communications · 2024Article
- Reversal of cognitive deficits in FUSNeurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Article
- Allele-Selective Thiomorpholino Antisense Oligonucleotides as a Therapeutic Approach for Fused-in-Sarcoma Amyotrophic Lateral Sclerosis.International journal of molecular sciences · 2024Article
- The Current Landscape of Hypotheses Describing the Contribution of CD4+ Heterogeneous Populations to ALS.Current issues in molecular biology · 2024Article
123 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
20 authors at 7 institutions in 1 country.
Funding
Abstract
Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause neurodegeneration. Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found that mutant FUS proteins formed a stable complex with WT FUS proteins and interfered with the normal interactions between FUS and histone deacetylase 1 (HDAC1). Consequently, FUS-R521C mice exhibited evidence of DNA damage as well as profound dendritic and synaptic phenotypes in brain and spinal cord. To provide insights into these defects, we screened neural genes for nucleotide oxidation and identified brain-derived neurotrophic factor (Bdnf) as a target of FUS-R521C-associated DNA damage and RNA splicing defects in mice. Compared with WT FUS, mutant FUS-R521C proteins formed a more stable complex with Bdnf RNA in electrophoretic mobility shift assays. Stabilization of the FUS/Bdnf RNA complex contributed to Bdnf splicing defects and impaired BDNF signaling through receptor TrkB. Exogenous BDNF only partially restored dendrite phenotype in FUS-R521C neurons, suggesting that BDNF-independent mechanisms may contribute to the defects in these neurons. Indeed, RNA-seq analyses of FUS-R521C spinal cords revealed additional transcription and splicing defects in genes that regulate dendritic growth and synaptic functions. Together, our results provide insight into how gain-of-function FUS mutations affect critical neuronal functions.
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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.