title: Ataxin-3 protein modification as a treatment strategy for spinocerebellar ataxia type 3: removal of the CAG containing exon.
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.
authors: Department of Human Genetics, Leiden University Medical Center, The Netherlands. M.M.Evers@lumc.nl
authors: Melvin M
authors: MM
authors: Evers
authors: Hoang-Dai
authors: HD
authors: Tran
authors: Ioannis
authors: I
authors: Zalachoras
authors: Barry A
authors: BA
authors: Pepers
authors: Onno C
authors: OC
authors: Meijer
authors: Johan T
authors: JT
authors: den Dunnen
authors: Gert-Jan B
authors: GJ
authors: van Ommen
authors: Annemieke
authors: A
authors: Aartsma-Rus
authors: Willeke M C
authors: WM
authors: van Roon-Mom
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D005091:Exons / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017827:Machado-Joseph Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D018911:Trinucleotide Repeats / Q000235:genetics*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D010455:Peptides; D012333:RNA, Messenger; D012097:Repressor Proteins; D025801:Ubiquitin; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: AON; ATXN3; Ataxin-3; CAG repeat; DMD; Duchenne muscular dystrophy; Exon skipping; ICV; MJD; Machado–Joseph disease; NES; NLS; PolyQ; Polyglutamine disorder; Polyglutamine repeat; RNA interference; RNAi; SCA3; SNP; Spinocerebellar ataxia type 3; UIMs; VCP; antisense oligonucleotide; ataxin-3; intra-cerebral ventricular; nuclear export signal; nuclear localization signal; polyglutamine; single nucleotide polymorphism; spinocerebellar ataxia type 3; ubiquitin interacting motifs; valosin containing protein