Journal article
Removal of the polyglutamine repeat of ataxin-3 by redirecting pre-mRNA processing
International Journal of Molecular Sciences, Vol.20(21), Article 5434
2019
Abstract
Spinocerebellar ataxia type 3 (SCA3) is a devastating neurodegenerative disease for which there is currently no cure, nor effective treatment strategy. One of nine polyglutamine disorders known to date, SCA3 is clinically heterogeneous and the main feature is progressive ataxia, which in turn affects speech, balance and gait of the affected individual. SCA3 is caused by an expanded polyglutamine tract in the ataxin-3 protein, resulting in conformational changes that lead to toxic gain of function. The expanded glutamine tract is located at the 5′ end of the penultimate exon (exon 10) of ATXN3 gene transcript. Other studies reported removal of the expanded glutamine tract using splice switching antisense oligonucleotides. Here, we describe improved efficiency in the removal of the toxic polyglutamine tract of ataxin-3 in vitro using phosphorodiamidate morpholino oligomers, when compared to antisense oligonucleotides composed of 2′-O-methyl modified bases on a phosphorothioate backbone. Significant downregulation of both the expanded and non-expanded protein was induced by the morpholino antisense oligomer, with a greater proportion of ataxin-3 protein missing the polyglutamine tract. With growing concerns over toxicity associated with long-term administration of phosphorothioate oligonucleotides, the use of a phosphorodiamidate morpholino oligomer may be preferable for clinical application. These results suggest that morpholino oligomers may provide greater therapeutic benefit for the treatment of spinocerebellar ataxia type 3, without toxic effects.
Details
- Title
- Removal of the polyglutamine repeat of ataxin-3 by redirecting pre-mRNA processing
- Authors/Creators
- C.S. McIntosh (Author/Creator) - Murdoch UniversityM.T. Aung-Htut (Author/Creator) - Murdoch UniversityS. Fletcher (Author/Creator) - Murdoch UniversityS.D. Wilton (Author/Creator) - Murdoch University
- Publication Details
- International Journal of Molecular Sciences, Vol.20(21), Article 5434
- Publisher
- MDPI AG
- Identifiers
- 991005543131207891
- Copyright
- © 2019 by the authors
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.52 Neurodegenerative Diseases
- 1.52.951 Huntington's and Ataxias
- Web Of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary
- ESI research areas
- Chemistry