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.
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 .
Which is the protein implicated in Spinocerebellar ataxia type 3?
Which is the protein implicated in Spinocerebellar ataxia type 3 ?
Ataxin-3
Ataxin-3