ArticleActa neuropathologica communications2020
RNA dependent suppression of C9orf72 ALS/FTD associated neurodegeneration by Matrin-3.
Article in Acta neuropathologica communications, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 26 citations in OpenAlex.
- MicroRNAs and Long Non-Coding RNAs Affect the Mechanisms Involved in Age-Related Neurodegeneration in a Manner Depending on RNA-Binding Proteins.Molecular neurobiology · 2026Review
- Dynamic changes in chromosome and nuclear architecture during maturation of normal and ALS C9orf72 motor neurons.bioRxiv : the preprint server for biology · 2025Article
- Blueprint of Collapse: Precision Biomarkers, Molecular Cascades, and the Engineered Decline of Fast-Progressing ALS.International journal of molecular sciences · 2025Review
- RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights.Molecular neurodegeneration · 2025Review
- Decoding Nucleotide Repeat Expansion Diseases: Novel Insights fromInternational journal of molecular sciences · 2024Review
- The role of Matrin-3 in physiology and its dysregulation in disease.Biochemical Society transactions · 2024Review
- Article
- SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration.Acta neuropathologica · 2023Article
- Article
- Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders.Frontiers in molecular neuroscience · 2023Review
- Partners in crime: Proteins implicated in RNA repeat expansion diseases.Wiley interdisciplinary reviews. RNA · 2022Review
- Matrin-3 dysfunction in myopathy and motor neuron degeneration.Neural regeneration research · 2022Article
- Review
- RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis.International journal of molecular sciences · 2021Review
- Fly for ALS: Drosophila modeling on the route to amyotrophic lateral sclerosis modifiers.Cellular and molecular life sciences : CMLS · 2021Review
- Interplay of RNA-Binding Proteins and microRNAs in Neurodegenerative Diseases.International journal of molecular sciences · 2021Review
- RNA-Binding Proteins and the Complex Pathophysiology of ALS.International journal of molecular sciences · 2021Review
- Altered Phase Separation and Cellular Impact inFrontiers in cellular neuroscience · 2021Article
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
The most common genetic cause of amyotrophic lateral sclerosis (ALS) is a GGGGCC (G4C2) hexanucleotide repeat expansions in first intron of the C9orf72 gene. The accumulation of repetitive RNA sequences can mediate toxicity potentially through the formation of intranuclear RNA foci that sequester key RNA-binding proteins (RBPs), and non-ATG mediated translation into toxic dipeptide protein repeats. However, the contribution of RBP sequestration to the mechanisms underlying RNA-mediated toxicity remain unknown. Here we show that the ALS-associated RNA-binding protein, Matrin-3 (MATR3), colocalizes with G4C2 RNA foci in patient tissues as well as iPSC-derived motor neurons harboring the C9orf72 mutation. Hyperexpansion of C9 repeats perturbed subcellular distribution and levels of endogenous MATR3 in C9-ALS patient-derived motor neurons. Interestingly, we observed that ectopic expression of human MATR3 strongly mitigates G4C2-mediated neurodegeneration in vivo. MATR3-mediated suppression of C9 toxicity was dependent on the RNA-binding domain of MATR3. Importantly, we found that expression of MATR3 reduced the levels of RAN-translation products in mammalian cells in an RNA-dependent manner. Finally, we have shown that knocking down endogenous MATR3 in C9-ALS patient-derived iPSC neurons decreased the presence of G4C2 RNA foci in the nucleus. Overall, these studies suggest that MATR3 genetically modifies the neuropathological and the pathobiology of C9orf72 ALS through modulating the RNA foci and RAN translation.
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