A Nurr1 point mutant, implicated in Parkinson's disease, uncouples ERK1/2-dependent regulation of tyrosine hydroxylase transcription.
Neurobiol Dis
; 29(1): 117-22, 2008 Jan.
Article
em En
| MEDLINE
| ID: mdl-17890097
ABSTRACT
The orphan nuclear receptor NURR1 is critical for the development of mesencephalic dopamine neurons and directly regulates tyrosine hydroxylase (TH) via specific NGFI-B response elements (NBRE). We identified a Parkinson's disease patient with a NURR1 mutation, resulting in a p.Ser125Cys change, immediately adjacent to the putative ERK1/2 phosphorylation site. Here we show, in dopaminergic SK-N-AS human neuroblastoma cells, that this substitution markedly attenuated NURR1-induced transcriptional activation through a human TH promoter NBRE. Furthermore, in SK-N-AS cells co-transfected with the dopamine-D2S receptor and NURR1, the dopamine-D2 agonist quinpirole stimulated ERK1/2 phosphorylation and enhanced transcriptional activation by wild-type NURR1 but not the p.Ser125Cys NURR1 mutant, and these actions were blocked by the specific MEK1/2 inhibitor PD98059. These results indicate that Ser125 is critical for basal and ERK1/2-induced NURR1 activity and suggest a role for this and other NURR1 mutations in the regulation of dopamine synthesis and predisposition to Parkinson's disease.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Tirosina 3-Mono-Oxigenase
/
Regulação da Expressão Gênica
/
Proteína Quinase 3 Ativada por Mitógeno
/
Proteínas de Ligação a DNA
/
Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Neurobiol Dis
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2008
Tipo de documento:
Article
País de afiliação:
Canadá