A splice intervention therapy for autosomal recessive juvenile Parkinson’s disease arising from Parkin mutations
Li, D., Aung-Htut, M.T., Ham, K.A.ORCID: 0000-0002-7036-5334, Fletcher, S. and Wilton, S.D.
(2020)
A splice intervention therapy for autosomal recessive juvenile Parkinson’s disease arising from Parkin mutations.
International Journal of Molecular Sciences, 21
(19).
Article 7282.
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Abstract
Parkin-type autosomal recessive juvenile-onset Parkinson’s disease is caused by mutations in the PRKN gene and accounts for 50% of all autosomal recessive Parkinsonism cases. Parkin is a neuroprotective protein that has dual functions as an E3 ligase in the ubiquitin–proteasome system and as a transcriptional repressor of p53. While genomic deletions of PRKN exon 3 disrupt the mRNA reading frame and result in the loss of functional parkin protein, deletions of both exon 3 and 4 maintain the reading frame and are associated with a later onset, milder disease progression, indicating this particular isoform retains some function. Here, we describe in vitro evaluation of antisense oligomers that restore functional parkin expression in cells derived from a Parkinson’s patient carrying a heterozygous PRKN exon 3 deletion, by inducing exon 4 skipping to correct the reading frame. We show that the induced PRKN transcript is translated into a shorter but semi-functional parkin isoform able to be recruited to depolarised mitochondria, and also transcriptionally represses p53 expression. These results support the potential use of antisense oligomers as a disease-modifying treatment for selected pathogenic PRKN mutations.
Item Type: | Journal Article |
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Murdoch Affiliation(s): | Centre for Molecular Medicine and Innovative Therapeutics (CMMIT) |
Publisher: | MDPI AG |
Copyright: | © 2020 by the authors |
URI: | http://researchrepository.murdoch.edu.au/id/eprint/58122 |
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