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

Neurobiology of Disease

Annemieke Aartsma-Rus¹  Gert-Jan B. van Ommen²  Ioannis Zalachoras³  Onno C. Meijer³  Johan T. den Dunnen⁴  Willeke M.C. van Roon-Mom⁴  Melvin M. Evers⁴  Hoang-Dai Tran⁴  Barry A. Pepers⁴ 

[1] Department of Clinical Genetics, Leiden University Medical Center, The Netherlands;Leiden Genome Technology Center, Leiden University Medical Center, The Netherlands;Department of Endocrinology, Leiden University Medical Center, The Netherlands;Department of Human Genetics, Leiden University Medical Center, The Netherlands;

关键词: Spinocerebellar ataxia type 3;    Polyglutamine disorder;    Ataxin-3;    Exon skipping;    CAG repeat;    Polyglutamine repeat;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown