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

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