Ataxin-3 protein modification as a treatment strategy for spinocerebellar ataxia type 3: Removal of the CAG containing exon

作者：Evers Melvin M; Tran Hoang Dai; Zalachoras Ioannis; Pepers Barry A; Meijer Onno C; den Dunnen Johan T; van Ommen Gert Jan B; Aartsma Rus Annemieke; van Roon Mom Willeke M C^*

来源：Neurobiology of Disease, 2013, 58: 49-56.

DOI：10.1016/j.nbd.2013.04.019

• Spinocerebellar ataxia type 3
• Polyglutamine disorder
• Ataxin-3
• Exon skipping
• CAG repeat
• Polyglutamine repeat

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.

• 出版日期2013-10