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A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson’s Disease Arising from Parkin Mutations

Authors: 
Li D, Aung-Htut MT, Ham KA, Fletcher S, Wilton SD
Citation: 
Int J Mol Sci. 2020;21(19):7282. doi:10.3390/ijms21197282
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.
Epub: 
Not Epub
Organism or Cell Type: 
cell culture: PRKN patient-derived fibroblasts
Delivery Method: 
Endo-Porter