ArticleNucleic acids research2023
Cytoplasmic aggregation of mutant FUS causes multistep RNA splicing perturbations in the course of motor neuron pathology.
Article in Nucleic acids research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 18 citations in OpenAlex.
- Multi-regional transcriptomic profiling reveals divergent molecular mechanisms in ALS-related neurodegeneration.PLoS genetics · 2026Article
- Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD.The Journal of clinical investigation · 2026Review
- Retrospective Study of the Physiological and Molecular Features of the S-FUS (1-359) Mouse Transgenic Model with an ALS-like Phenotype: Lifespan, Body Weight Dynamics, Movement Disorders, and Dysregulation of the Dopaminergic System.Journal of molecular neuroscience : MN · 2026Article
- Splicing factor FUS facilitates the progression of PIT1-lineage PitNETs by upregulating MDM2.Theranostics · 2026Article
- Protein Structure-based FUS Mutational Subtypes Are Associated With Protein Mislocalization in Amyotrophic Lateral Sclerosis Patients.Molecular neurobiology · 2025Article
- G-quadruplex structural motifs modulate protein-RNA interactions within the transcriptome.Genome biology · 2025Article
- Blueprint of Collapse: Precision Biomarkers, Molecular Cascades, and the Engineered Decline of Fast-Progressing ALS.International journal of molecular sciences · 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
- Emerging biomarkers in amyotrophic lateral sclerosis: from pathogenesis to clinical applications.Frontiers in molecular biosciences · 2025Review
- Crosstalk between RNA-binding proteins and non-coding RNAs in tumors: molecular mechanisms, and clinical significance.International journal of biological sciences · 2025Review
- Circular RNA in cancer.Nature reviews. Cancer · 2024Review
- hnRNP R promotes O-GlcNAcylation of eIF4G and facilitates axonal protein synthesis.Nature communications · 2024Article
- An impaired splicing program underlies differentiation defects in hSOD1Cellular and molecular life sciences : CMLS · 2023Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Dysfunction of the RNA-binding protein (RBP) FUS implicated in RNA metabolism can cause amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Mutations affecting FUS nuclear localization can drive RNA splicing defects and stimulate the formation of non-amyloid inclusions in affected neurons. However, the mechanism by which FUS mutations contribute to the development of ALS remains uncertain. Here we describe a pattern of RNA splicing changes in the dynamics of the continuous proteinopathy induced by mislocalized FUS. We show that the decrease in intron retention of FUS-associated transcripts represents the hallmark of the pathogenesis of ALS and is the earliest molecular event in the course of progression of the disease. As FUS aggregation increases, the pattern of RNA splicing changes, becoming more complex, including a decrease in the inclusion of neuron-specific microexons and induction of cryptic exon splicing due to the sequestration of additional RBPs into FUS aggregates. Crucially, the identified features of the pathological splicing pattern are also observed in ALS patients in both sporadic and familial cases. Our data provide evidence that both a loss of nuclear FUS function due to mislocalization and the subsequent cytoplasmic aggregation of mutant protein lead to the disruption of RNA splicing in a multistep fashion during FUS aggregation.
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