ArticleActa neuropathologica communications2019
ALS-linked FUS mutations confer loss and gain of function in the nucleus by promoting excessive formation of dysfunctional paraspeckles.
Article in Acta neuropathologica communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed, 149 citations in OpenAlex.
- Article
- Mapping interactions between disordered regions reveals promiscuity in biomolecular condensate formation.Nature communications · 2026Article
- Visualizing TERRA RNA G-quadruplex Unfolding in FUS Biomolecular Condensates.Journal of molecular biology · 2026Article
- Paraspeckle condensation is controlled via TDP-43 polymerization and linked to neuroprotection.Nature cell biology · 2026Article
- Linking TDP-43-regulated paraspeckle condensation to neuroprotection.Nature cell biology · 2026Article
- Human FUS is toxic via association with RNA polymerase II in Drosophila.Cell death & disease · 2026Article
- Somatic gene mutations in the motor cortex of patients with sporadic amyotrophic lateral sclerosis.Brain : a journal of neurology · 2026Article
- 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
- Visualizing TERRA RNA G-quadruplex unfolding in FUS biomolecular condensates.bioRxiv : the preprint server for biology · 2025Article
- Enhanced hybridization-proximity labeling discovers protein interactomes of single RNA molecules.Nature communications · 2025Article
- Dominant-negative isoform of TDP-43 is regulated by ALS-linked RNA-binding proteins.The Journal of cell biology · 2025Article
- LncRNA levels in the central nervous system as novel potential players and biomarkers in amyotrophic lateral sclerosis.Non-coding RNA research · 2025Article
- G-quadruplex structural motifs modulate protein-RNA interactions within the transcriptome.Genome biology · 2025Article
- ALS-associated RNA-binding proteins promote UNC13A transcription through REST downregulation.The EMBO journal · 2025Article
- M6A-dependent RNA condensation underlies FUS autoregulation and can be harnessed for ALS therapy development.Science advances · 2025Article
- The Role of Non-Coding RNAs in ALS.Genes · 2025Review
- DNA nanoflower Oligo-PROTAC for targeted degradation of FUS to treat neurodegenerative diseases.Nature communications · 2025Article
- Rare Diseases, Spotlighting Amyotrophic Lateral Sclerosis, Huntington's Disease, and Myasthenia Gravis: Insights from Landscape Analysis of Current Research.Biochemistry · 2025Review
- Distinct expression of NEAT1 isoforms in Parkinson's disease models suggests different roles of the variants during the disease course.Scientific reports · 2025Article
- Exploring epigenetic modifications as potential biomarkers and therapeutic targets in amyotrophic lateral sclerosis.Journal of neurology · 2025Review
29 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 5 institutions in 4 countries.
Funding
Abstract
Mutations in the FUS gene cause amyotrophic lateral sclerosis (ALS-FUS). Mutant FUS is known to confer cytoplasmic gain of function but its effects in the nucleus are less understood. FUS is an essential component of paraspeckles, subnuclear bodies assembled on a lncRNA NEAT1. Paraspeckles may play a protective role specifically in degenerating spinal motor neurons. However it is still unknown how endogenous levels of mutant FUS would affect NEAT1/paraspeckles. Using novel cell lines with the FUS gene modified by CRISPR/Cas9 and human patient fibroblasts, we found that endogenous levels of mutant FUS cause accumulation of NEAT1 isoforms and paraspeckles. However, despite only mild cytoplasmic mislocalisation of FUS, paraspeckle integrity is compromised in these cells, as confirmed by reduced interaction of mutant FUS with core paraspeckle proteins NONO and SFPQ and increased NEAT1 extractability. This results in NEAT1 localisation outside paraspeckles, especially prominent under conditions of paraspeckle-inducing stress. Consistently, paraspeckle-dependent microRNA production, a readout for functionality of paraspeckles, is impaired in cells expressing mutant FUS. In line with the cellular data, we observed paraspeckle hyper-assembly in spinal neurons of ALS-FUS patients. Therefore, despite largely preserving its nuclear localisation, mutant FUS leads to loss (dysfunctional paraspeckles) and gain (excess of free NEAT1) of function in the nucleus. Perturbed fine structure and functionality of paraspeckles accompanied by accumulation of non-paraspeckle NEAT1 may contribute to the disease severity in ALS-FUS.
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