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.