A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson's Disease Arising from Parkin Mutations.
Int J Mol Sci
; 21(19)2020 Oct 01.
Article
em En
| MEDLINE
| ID: mdl-33019779
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
RNA Mensageiro
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Oligonucleotídeos Antissenso
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Deleção de Sequência
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Processamento Alternativo
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Transtornos Parkinsonianos
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Ubiquitina-Proteína Ligases
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Morfolinos
Limite:
Humans
Idioma:
En
Revista:
Int J Mol Sci
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Austrália