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 <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 sy...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-10-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/19/7282 |
| Summary: | 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. |
|---|---|
| ISSN: | 1661-6596 1422-0067 |