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Open AccessArticle

Removal of the Polyglutamine Repeat of Ataxin-3 by Redirecting pre-mRNA Processing

1
Molecular Therapy Laboratory, Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Health Research Building, Discovery Way, Murdoch WA 6150, Australia
2
Perron Institute for Neurological and Translational Science, Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands WA 6009, Australia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(21), 5434; https://doi.org/10.3390/ijms20215434
Received: 10 October 2019 / Revised: 28 October 2019 / Accepted: 29 October 2019 / Published: 31 October 2019
(This article belongs to the Section Molecular Genetics and Genomics)
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. View Full-Text
Keywords: spinocerebellar ataxia type 3; antisense oligonucleotides; exon skipping; ataxin-3; polyglutamine; phosphorodiamidate morpholino oligomer spinocerebellar ataxia type 3; antisense oligonucleotides; exon skipping; ataxin-3; polyglutamine; phosphorodiamidate morpholino oligomer
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McIntosh, C.S.; Aung-Htut, M.T.; Fletcher, S.; Wilton, S.D. Removal of the Polyglutamine Repeat of Ataxin-3 by Redirecting pre-mRNA Processing. Int. J. Mol. Sci. 2019, 20, 5434.

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