کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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3070697 | 1580735 | 2008 | 6 صفحه PDF | دانلود رایگان |
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.
Journal: Neurobiology of Disease - Volume 29, Issue 1, January 2008, Pages 117–122