Differential expression of PARK2 splice isoforms in an in vitro model of dopaminergic-like neurons exposed to toxic insults mimicking Parkinson's disease.
J Cell Biochem
; 119(1): 1062-1073, 2018 01.
Article
em En
| MEDLINE
| ID: mdl-28688199
ABSTRACT
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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Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
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Processamento Alternativo
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Ubiquitina-Proteína Ligases
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Modelos Biológicos
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Neurotoxinas
Tipo de estudo:
Etiology_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article