ArticleScientific reports2016
Antisense oligonucleotide-mediated exon skipping as a strategy to reduce proteolytic cleavage of ataxin-3.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 36 citations in OpenAlex.
- Review
- ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Evaluation of Cerebellar Ataxic Patients.Neurologic clinics · 2023Review
- Review
- Calpain-mediated proteolysis as driver and modulator of polyglutamine toxicity.Frontiers in molecular neuroscience · 2022Review
- Induction of cryptic pre-mRNA splice-switching by antisense oligonucleotides.Scientific reports · 2021Article
- New Perspectives of Gene Therapy on Polyglutamine Spinocerebellar Ataxias: From Molecular Targets to Novel Nanovectors.Pharmaceutics · 2021Review
- Selective Neuron Vulnerability in Common and Rare Diseases-Mitochondria in the Focus.Frontiers in molecular biosciences · 2021Review
- Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3.Science translational medicine · 2020Article
- Calpain-1 ablation partially rescues disease-associated hallmarks in models of Machado-Joseph disease.Human molecular genetics · 2020Article
- Pathogenesis of SCA3 and implications for other polyglutamine diseases.Neurobiology of disease · 2020Review
- Removal of the Polyglutamine Repeat of Ataxin-3 by Redirecting pre-mRNA Processing.International journal of molecular sciences · 2019Article
- Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Spinocerebellar ataxia: an update.Journal of neurology · 2019Review
- Intravenously Administered Novel Liposomes, DCL64, Deliver Oligonucleotides to Cerebellar Purkinje Cells.Cerebellum (London, England) · 2019Article
- Antisense-mediated splice intervention to treat human disease: the odyssey continues.F1000Research · 2019Review
- Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model.Molecular neurodegeneration · 2018Article
- RD-Connect, NeurOmics and EURenOmics: collaborative European initiative for rare diseases.European journal of human genetics : EJHG · 2018Article
- Intracerebroventricular Administration of a 2'-O-Methyl Phosphorothioate Antisense Oligonucleotide Results in Activation of the Innate Immune System in Mouse Brain.Nucleic acid therapeutics · 2018Article
- Antisense Oligonucleotide-Mediated Removal of the Polyglutamine Repeat in Spinocerebellar Ataxia Type 3 Mice.Molecular therapy. Nucleic acids · 2017Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Spinocerebellar ataxia type-3 (SCA3) is a neurodegenerative disorder caused by a polyglutamine repeat expansion in the ataxin-3 protein. Cleavage of mutant ataxin-3 by proteolytic enzymes yields ataxin-3 fragments containing the polyglutamine stretch. These shorter ataxin-3 fragments are thought to be involved in SCA3 pathogenesis due to their increased cellular toxicity and their involvement in formation of the characteristic neuronal aggregates. As a strategy to prevent formation of toxic cleavage fragments, we investigated an antisense oligonucleotide-mediated modification of the ataxin-3 pre-mRNA through exon skipping of exon 8 and 9, resulting in the removal of a central 88 amino acid region of the ataxin-3 protein. This removed protein region contains several predicted cleavage sites and two ubiquitin-interacting motifs. In contrast to unmodified mutant ataxin-3, the internally truncated ataxin-3 protein did not give rise to potentially toxic cleavage fragments when incubated with caspases. In vitro experiments did not show cellular toxicity of the modified ataxin-3 protein. However, the modified protein was incapable of binding poly-ubiquitin chains, which may interfere with its normal deubiquitinating function. Low exon skipping efficiencies combined with reduction in important ataxin-3 protein functions suggest that skipping of exon 8 and 9 is not a viable therapeutic option for SCA3.
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