ArticleProceedings of the National Academy of Sciences of the United States of America2013
Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 328 papers.
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328 citing papers in PubMed, 528 citations in OpenAlex.
- Expanded Polyglycine Protein Aggregates Alter the RNA Splicing Profile into a Premature State Partially via Sequestering SF3B4.Neuroscience bulletin · 2026Article
- ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties.bioRxiv : the preprint server for biology · 2026Article
- The HTT1a protein initiates HTT aggregation in a knock-in mouse model of Huntington's disease.Brain : a journal of neurology · 2026Article
- Targeting toxic HTT1a could be the key to treating Huntington disease.Nature reviews. Neurology · 2026Article
- The DNA/RNA autophagy protein SIDT2 as a novel neuropathological hallmark in Huntington disease.Brain pathology (Zurich, Switzerland) · 2026Article
- Human-specific sequence features in HTT exon 1 promote toxic misprocessing via splicing factor SRSF7.Nature communications · 2026Article
- In vivo CRISPR base editing for treatment of Huntington's disease.Nature biomedical engineering · 2026Article
- Somatic CRISPR editing ofbioRxiv : the preprint server for biology · 2026Article
- Targeting UCHL3 attenuates pathological markers in neuronal models of Huntington's disease.Brain : a journal of neurology · 2026Article
- Lipid composition controls the huntingtin exon 1 membrane-association and differentially modulates its flanking regions' dynamics.Protein science : a publication of the Protein Society · 2026Article
- The contribution of short tandem repeats to splicing variation in the human cortex.bioRxiv : the preprint server for biology · 2026Article
- Molecular features of a Huntington's disease knock-in minipig.Disease models & mechanisms · 2026Article
- Modest rescue of RBFOX1 splicing function attenuates Huntington's disease features.Molecular medicine (Cambridge, Mass.) · 2026Article
- CAG-targeting artificial miRNA with reduced off-target risk for efficient lowering of pathogenic polyglutamine proteins.NAR molecular medicine · 2026Article
- Proteoforms as the true units of physiological function.European journal of applied physiology · 2026Review
- Astrocyte heterogeneity and gliosis in Huntington's disease: Histopathological insights into striatal and white matter pathology.Histology and histopathology · 2026Review
- Prevention of ubiquitination at K6 and K9 in mutant huntingtin exacerbates disease pathology in a knock-in mouse model.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Nucleic acid therapeutics in neurodegenerative disorders: emerging technologies and clinical landscape.Molecular neurodegeneration advances · 2026Review
- Huntington disease: somatic expansion, pathobiology and therapeutics.Nature reviews. Neurology · 2026Review
- Enhancing the detection of HTT1a with neoepitope antibodies in mouse models of Huntington's disease.Brain communications · 2026Article
268 more citing papers are in PubMed but not listed here.
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13 authors at 6 institutions in 4 countries.
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Abstract
Huntington disease (HD) is a devastating, late-onset, inherited neurodegenerative disorder that manifests with personality changes, movement disorders, and cognitive decline. It is caused by a CAG repeat expansion in exon 1 of the HTT gene that translates to a polyglutamine tract in the huntingtin protein (HTT). The formation of HTT fragments has been implicated as an essential step in the molecular pathogenesis of HD and several proteases that cleave HTT have been identified. However, the importance of smaller N-terminal fragments has been highlighted by their presence in HD postmortem brains and by the fact that nuclear inclusions are only detected by antibodies to the N terminus of HTT. Despite an intense research effort, the precise length of these fragments and the mechanism by which they are generated remains unknown. Here we show that CAG repeat length-dependent aberrant splicing of exon 1 HTT results in a short polyadenylated mRNA that is translated into an exon 1 HTT protein. Given that mutant exon 1 HTT proteins have consistently been shown to be highly pathogenic in HD mouse models, the aberrant splicing of HTT mRNA provides a mechanistic basis for the molecular pathogenesis of HD. RNA-targeted therapeutic strategies designed to lower the levels of HTT are under development. Many of these approaches would not prevent the production of exon 1 HTT and should be reviewed in light of our findings.
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