ArticleHuman molecular genetics2015
RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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71 citing papers in PubMed, 94 citations in OpenAlex.
- Translation of expanded CGG repeats in LRP12 associated oculopharyngodistal myopathy.Acta neuropathologica communications · 2026Article
- Integrative transcriptome-wide association analyses reveal PRKCG-linked GABAergic dysfunction in Fragile X-associated tremor/ataxia syndrome.Nature communications · 2026Article
- Modelling fragile X-associated neuropsychiatric disorders in young inducible 90CGG premutation mice.Brain : a journal of neurology · 2025Article
- Nigrostriatal Degeneration Underpins Sensorimotor Dysfunction in an Inducible Mouse Model of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).International journal of molecular sciences · 2025Article
- Stress granule formation helps to mitigate neurodegeneration.Nucleic acids research · 2024Article
- Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats.Nucleic acids research · 2024Article
- Bridging the gap: R-loop mediated genomic instability and its implications in neurological diseases.Epigenomics · 2024Review
- Review
- Stress granule formation helps to mitigate neurodegeneration.bioRxiv : the preprint server for biology · 2023Article
- Review
- Native functions of short tandem repeats.eLife · 2023Article
- Toxicities of amyloid-beta and tau protein are reciprocally enhanced in theNeural regeneration research · 2022Article
- CGG repeats trigger translational frameshifts that generate aggregation-prone chimeric proteins.Nucleic acids research · 2022Article
- Mechanistic convergence across initiation sites for RAN translation in fragile X associated tremor ataxia syndrome.Human molecular genetics · 2022Article
- Identification ofProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Article
- Neurodegenerative diseases associated with non-coding CGG tandem repeat expansions.Nature reviews. Neurology · 2022Review
- RAN proteins in neurodegenerative disease: Repeating themes and unifying therapeutic strategies.Current opinion in neurobiology · 2022Review
- Clinical and mechanism advances of neuronal intranuclear inclusion disease.Frontiers in aging neuroscience · 2022Review
- RNA Helicases in Microsatellite Repeat Expansion Disorders and Neurodegeneration.Frontiers in genetics · 2022Review
11 more citing papers are in PubMed but not listed here.
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7 authors at 3 institutions in 1 country.
Funding
Abstract
Fragile X-associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide repeat expansion in the 5' UTR of the Fragile X gene, FMR1. FXTAS is thought to arise primarily from an RNA gain-of-function toxicity mechanism. However, recent studies demonstrate that the repeat also elicits production of a toxic polyglycine protein, FMRpolyG, via repeat-associated non-AUG (RAN)-initiated translation. Pathologically, FXTAS is characterized by ubiquitin-positive intranuclear neuronal inclusions, raising the possibility that failure of protein quality control pathways could contribute to disease pathogenesis. To test this hypothesis, we used Drosophila- and cell-based models of CGG-repeat-associated toxicity. In Drosophila, ubiquitin proteasome system (UPS) impairment led to enhancement of CGG-repeat-induced degeneration, whereas overexpression of the chaperone protein HSP70 suppressed this toxicity. In transfected mammalian cells, CGG repeat expression triggered accumulation of a UPS reporter in a length-dependent fashion. To delineate the contributions from CGG repeats as RNA from RAN translation-associated toxicity, we enhanced or impaired the production of FMRpolyG in these models. Driving expression of FMRpolyG enhanced induction of UPS impairment in cell models, while prevention of RAN translation attenuated UPS impairment in cells and suppressed the genetic interaction with UPS manipulation in Drosophila. Taken together, these findings suggest that CGG repeats induce UPS impairment at least in part through activation of RAN translation.
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