Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6022211 | Neurobiology of Disease | 2013 | 8 Pages |
Abstract
Spinocerebellar ataxia type 3 is caused by a polyglutamine expansion in the ataxin-3 protein, resulting in gain of toxic function of the mutant protein. The expanded glutamine stretch in the protein is the result of a CAG triplet repeat expansion in the penultimate exon of the ATXN3 gene. Several gene silencing approaches to reduce mutant ataxin-3 toxicity in this disease aim to lower ataxin-3 protein levels, but since this protein is involved in deubiquitination and proteasomal protein degradation, its long-term silencing might not be desirable. Here, we propose a novel protein modification approach to reduce mutant ataxin-3 toxicity by removing the toxic polyglutamine repeat from the ataxin-3 protein through antisense oligonucleotide-mediated exon skipping while maintaining important wild type functions of the protein. In vitro studies showed that exon skipping did not negatively impact the ubiquitin binding capacity of ataxin-3. Our in vivo studies showed no toxic properties of the novel truncated ataxin-3 protein. These results suggest that exon skipping may be a novel therapeutic approach to reduce polyglutamine-induced toxicity in spinocerebellar ataxia type 3.
Keywords
DMDSCA3ATXN3MJDAtaxin-3VCPNLSPolyQICVPolyglutamine repeatnESUIMsantisense oligonucleotideRNA interferenceRNAiMachado–Joseph diseaseCAG repeatDuchenne muscular dystrophynuclear export signalnuclear localization signalSpinocerebellar Ataxia Type 3Valosin containing proteinexon skippingPolyglutamineSingle nucleotide polymorphismSNPAON
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Authors
Melvin M. Evers, Hoang-Dai Tran, Ioannis Zalachoras, Barry A. Pepers, Onno C. Meijer, Johan T. den Dunnen, Gert-Jan B. van Ommen, Annemieke Aartsma-Rus, Willeke M.C. van Roon-Mom,