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

• Main Authors: Dunhui Li, May T. Aung-Htut, Kristin A. Ham, Sue Fletcher, Steve D. Wilton
• Format: Article
• Language: English
• Published: MDPI AG 2020-10-01
• Series: International Journal of Molecular Sciences
• Subjects: antisense oligonucleotides; exon skipping; juvenile-onset Parkinson’s disease; precision medicine
• Online Access: https://www.mdpi.com/1422-0067/21/19/7282

Parkin-type autosomal recessive juvenile-onset Parkinson’s disease is caused by mutations in the <i>PRKN</i> 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 <i>p53</i>. While genomic deletions of <i>PRKN</i> 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 <i>PRKN</i> exon 3 deletion, by inducing exon 4 skipping to correct the reading frame. We show that the induced <i>PRKN</i> transcript is translated into a shorter but semi-functional parkin isoform able to be recruited to depolarised mitochondria, and also transcriptionally represses <i>p53</i> expression. These results support the potential use of antisense oligomers as a disease-modifying treatment for selected pathogenic <i>PRKN</i> mutations.