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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/19/7282 |
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| author | Dunhui Li May T. Aung-Htut Kristin A. Ham Sue Fletcher Steve D. Wilton |
| author_facet | Dunhui Li May T. Aung-Htut Kristin A. Ham Sue Fletcher Steve D. Wilton |
| author_sort | Dunhui Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T15:53:30Z |
| format | Article |
| id | doaj.art-0312c6bdfa8541dcbb44528670a3fb3e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:53:30Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-0312c6bdfa8541dcbb44528670a3fb3e2023-11-20T15:51:54ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012119728210.3390/ijms21197282A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson’s Disease Arising from Parkin MutationsDunhui Li0May T. Aung-Htut1Kristin A. Ham2Sue Fletcher3Steve D. Wilton4Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth 6150, AustraliaCentre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth 6150, AustraliaCentre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth 6150, AustraliaCentre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth 6150, AustraliaCentre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth 6150, AustraliaParkin-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.https://www.mdpi.com/1422-0067/21/19/7282antisense oligonucleotidesexon skippingjuvenile-onset Parkinson’s diseaseprecision medicine |
| spellingShingle | Dunhui Li May T. Aung-Htut Kristin A. Ham Sue Fletcher Steve D. Wilton A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson’s Disease Arising from Parkin Mutations International Journal of Molecular Sciences antisense oligonucleotides exon skipping juvenile-onset Parkinson’s disease precision medicine |
| title | A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson’s Disease Arising from Parkin Mutations |
| title_full | A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson’s Disease Arising from Parkin Mutations |
| title_fullStr | A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson’s Disease Arising from Parkin Mutations |
| title_full_unstemmed | A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson’s Disease Arising from Parkin Mutations |
| title_short | A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson’s Disease Arising from Parkin Mutations |
| title_sort | splice intervention therapy for autosomal recessive juvenile parkinson s disease arising from parkin mutations |
| topic | antisense oligonucleotides exon skipping juvenile-onset Parkinson’s disease precision medicine |
| url | https://www.mdpi.com/1422-0067/21/19/7282 |
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