ArticleEuropean journal of human genetics : EJHG2014
Allele-specific silencing of mutant Ataxin-7 in SCA7 patient-derived fibroblasts.
Article in European journal of human genetics : EJHG, 2014. 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, 33 citations in OpenAlex.
- Experimental Models to Study Polyglutamine Spinocerebellar Ataxias: From Mechanisms to Therapeutic Developments.Cerebellum (London, England) · 2026Review
- Molecular hallmarks of neurodegeneration in polyglutamine spinocerebellar ataxias.Cell death & disease · 2025Review
- Chemical engineering of therapeutic siRNAs for allele-specific gene silencing in Huntington's disease models.Nature communications · 2022Article
- Development of versatile allele-specific siRNAs able to silence all the dominant dynamin 2 mutations.Molecular therapy. Nucleic acids · 2022Article
- The HSP40 chaperone Ydj1 drives amyloid beta 42 toxicity.EMBO molecular medicine · 2022Article
- New Perspectives of Gene Therapy on Polyglutamine Spinocerebellar Ataxias: From Molecular Targets to Novel Nanovectors.Pharmaceutics · 2021Review
- Current Status of Gene Therapy Research in Polyglutamine Spinocerebellar Ataxias.International journal of molecular sciences · 2021Review
- Molecular and electrophysiological features of spinocerebellar ataxia type seven in induced pluripotent stem cells.PloS one · 2021Article
- Universal RNAi Triggers for the Specific Inhibition of Mutant Huntingtin, Atrophin-1, Ataxin-3, and Ataxin-7 Expression.Molecular therapy. Nucleic acids · 2020Article
- Exploring the Potential of Small Molecule-Based Therapeutic Approaches for Targeting Trinucleotide Repeat Disorders.Molecular neurobiology · 2020Review
- Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Recent advances in molecular therapies for neurological disease: triplet repeat disorders.Human molecular genetics · 2019Review
- Ophthalmological and Neurologic Manifestations in Pre-clinical and Clinical Phases of Spinocerebellar Ataxia Type 7.Cerebellum (London, England) · 2019Article
- Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Knockdown and replacement therapy mediated by artificial mirtrons in spinocerebellar ataxia 7.Nucleic acids research · 2017Article
- Article
- Precision medicine in spinocerebellar ataxias: treatment based on common mechanisms of disease.Annals of translational medicine · 2016Review
- CADASIL and CARASIL.Brain pathology (Zurich, Switzerland) · 2014Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Polyglutamine (polyQ) disorders are inherited neurodegenerative conditions defined by a common pathogenic CAG repeat expansion leading to a toxic gain-of-function of the mutant protein. Consequences of this toxicity include activation of heat-shock proteins (HSPs), impairment of the ubiquitin-proteasome pathway and transcriptional dysregulation. Several studies in animal models have shown that reducing levels of toxic protein using small RNAs would be an ideal therapeutic approach for such disorders, including spinocerebellar ataxia-7 (SCA7). However, testing such RNA interference (RNAi) effectors in genetically appropriate patient cell lines with a disease-relevant phenotype has yet to be explored. Here, we have used primary adult dermal fibroblasts from SCA7 patients and controls to assess the endogenous allele-specific silencing of ataxin-7 by two distinct siRNAs. We further identified altered expression of two disease-relevant transcripts in SCA7 patient cells: a twofold increase in levels of the HSP DNAJA1 and a twofold decrease in levels of the de-ubiquitinating enzyme, UCHL1. After siRNA treatment, the expression of both genes was restored towards normal levels. To our knowledge, this is the first time that allele-specific silencing of mutant ataxin-7, targeting a common SNP, has been demonstrated in patient cells. These findings highlight the advantage of an allele-specific RNAi-based therapeutic approach, and indicate the value of primary patient-derived cells as useful models for mechanistic studies and for measuring efficacy of RNAi effectors on a patient-to-patient basis in the polyQ diseases.
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