ArticleHuman molecular genetics2014
TDP-43 suppresses CGG repeat-induced neurotoxicity through interactions with HnRNP A2/B1.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 61 citations in OpenAlex.
- Article
- Integrative transcriptome-wide association analyses reveal PRKCG-linked GABAergic dysfunction in Fragile X-associated tremor/ataxia syndrome.Nature communications · 2026Article
- From development to disease: the neuronal role of hnRNPs through the lens ofFrontiers in cell and developmental biology · 2026Review
- RNA/DNA-binding protein TDP43 regulates DNA mismatch repair genes with implications for genome stability.Nucleic acids research · 2025Article
- RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.bioRxiv : the preprint server for biology · 2025Article
- Review
- Dysregulated NFrontiers of medicine · 2024Article
- Review
- Native functions of short tandem repeats.eLife · 2023Article
- Evidence for a fragile X messenger ribonucleoprotein 1 (FMR1) mRNA gain-of-function toxicity mechanism contributing to the pathogenesis of fragile X-associated premature ovarian insufficiency.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Partners in crime: Proteins implicated in RNA repeat expansion diseases.Wiley interdisciplinary reviews. RNA · 2022Review
- NOS1AP is a novel molecular target and critical factor in TDP-43 pathology.Brain communications · 2022Article
- Trinucleotide CGG Repeat Diseases: An Expanding Field of Polyglycine Proteins?Frontiers in genetics · 2022Review
- Heterogeneous Nuclear Ribonucleoproteins: Implications in Neurological Diseases.Molecular neurobiology · 2021Review
- The Regulatory Role of RNA Metabolism Regulator TDP-43 in Human Cancer.Frontiers in oncology · 2021Review
- Contribution of RNA/DNA Binding Protein Dysfunction in Oligodendrocytes in the Pathogenesis of the Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration Spectrum Diseases.Frontiers in neuroscience · 2021Review
- Insight Into Spinocerebellar Ataxia Type 31 (SCA31) FromFrontiers in neuroscience · 2021Review
- Therapeutic Development for CGG Repeat Expansion-Associated Neurodegeneration.Frontiers in cellular neuroscience · 2021Article
- CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome.Science advances · 2021Article
- Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotypic profiles in Drosophila.Acta neuropathologica communications · 2020Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
Nucleotide repeat expansions can elicit neurodegeneration as RNA by sequestering specific RNA-binding proteins, preventing them from performing their normal functions. Conversely, mutations in RNA-binding proteins can trigger neurodegeneration at least partly by altering RNA metabolism. In Fragile X-associated tremor/ataxia syndrome (FXTAS), a CGG repeat expansion in the 5'UTR of the fragile X gene (FMR1) leads to progressive neurodegeneration in patients and CGG repeats in isolation elicit toxicity in Drosophila and other animal models. Here, we identify the amyotrophic lateral sclerosis (ALS)-associated RNA-binding protein TAR DNA-binding protein (TDP-43) as a suppressor of CGG repeat-induced toxicity in a Drosophila model of FXTAS. The rescue appears specific to TDP-43, as co-expression of another ALS-associated RNA-binding protein, FUS, exacerbates the toxic effects of CGG repeats. Suppression of CGG RNA toxicity was abrogated by disease-associated mutations in TDP-43. TDP-43 does not co-localize with CGG RNA foci and its ability to bind RNA is not required for rescue. TDP-43-dependent rescue does, however, require fly hnRNP A2/B1 homologues Hrb87F and Hrb98DE. Deletions in the C-terminal domain of TDP-43 that preclude interactions with hnRNP A2/B1 abolish TDP-43-dependent rescue of CGG repeat toxicity. In contrast, suppression of CGG repeat toxicity by hnRNP A2/B1 is not affected by RNAi-mediated knockdown of the fly TDP-43 orthologue, TBPH. Lastly, TDP-43 suppresses CGG repeat-triggered mis-splicing of an hnRNP A2/B1-targeted transcript. These data support a model in which TDP-43 suppresses CGG-mediated toxicity through interactions with hnRNP A2/B1 and suggest a convergence of pathogenic cascades between repeat expansion disorders and RNA-binding proteins implicated in neurodegenerative disease.
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