Journal article
A splice intervention therapy for autosomal recessive juvenile Parkinson’s disease arising from Parkin mutations
International Journal of Molecular Sciences, Vol.21(19), Article 7282
2020
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.
Details
- Title
- A splice intervention therapy for autosomal recessive juvenile Parkinson’s disease arising from Parkin mutations
- Authors/Creators
- D. Li (Author/Creator) - Murdoch UniversityM.T. Aung-Htut (Author/Creator) - Murdoch UniversityK.A. Ham (Author/Creator) - Murdoch UniversityS. Fletcher (Author/Creator) - Murdoch UniversityS.D. Wilton (Author/Creator) - Murdoch University
- Publication Details
- International Journal of Molecular Sciences, Vol.21(19), Article 7282
- Publisher
- MDPI AG
- Identifiers
- 991005542671207891
- Copyright
- © 2020 by the authors
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics
- Language
- English
- Resource Type
- Journal article
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
Source: InCites
Metrics
36 File views/ downloads
92 Record Views
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.52 Neurodegenerative Diseases
- 1.52.67 Parkinson's Disease
- Web Of Science research areas
- Biochemistry & Molecular Biology
- Chemistry, Multidisciplinary
- ESI research areas
- Chemistry