Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in PARK2 (or parkin) are responsible for 50% of cases of autosomal-recessive juvenile-onset Parkinson's disease (PD). To date, 21 alternative splice variants of the human gene have been cloned. Yet most studies have focused on the full-length protein, whereas the spectrum of the parkin isoforms expressed in PD has never been investigated. In this study, the role of parkin proteins in PD neurodegeneration was explored for the first time by analyzing their expression profile in an in vitro model of PD. To do so, undifferentiated and all-trans-retinoic-acid (RA)-differentiated SH-SY5Y cells (which thereby acquire a PD-like phenotype) were exposed to PD-mimicking neurotoxins: 1-methyl-4-phenylpyridinium (MPP+ ) and 6-hydroxydopamine (6-OHDA) are widely used in PD models, whereas carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and carbobenzoxy-Leu-Leu-leucinal (MG132) interfere, respectively, with mitochondrial mitophagy and proteasomal degradation. Following treatment with each neurotoxin H1, the first parkin isoform to be cloned, was down-regulated compared to the respective controls both in undifferentiated and RA-differentiated cells. In contrast, the expression pattern of the minor splice isoforms varied as a function of the compound used: it was largely unchanged in both cell cultures (eg, H21-H6, H12, XP isoform) or it showed virtually opposite alterations in undifferentiated and RA-differentiated cells (eg, H20 and H3 isoform). This complex picture suggests that up- or down-regulation may be a direct effect of toxin exposure, and that the different isoforms may exert different actions in neurodegeneration via modulation of different molecular pathways.
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PMID:Differential expression of PARK2 splice isoforms in an in vitro model of dopaminergic-like neurons exposed to toxic insults mimicking Parkinson's disease. 2868 99

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.
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PMID:A Splice Intervention Therapy for Autosomal Recessive Juvenile Parkinson's Disease Arising from Parkin Mutations. 3301 79