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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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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
Murdoch Affiliation(s): Centre for Molecular Medicine and Innovative Therapeutics (CMMIT)
Publisher: MDPI AG
Copyright: © 2020 by the authors
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