| 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. |
| Authors | Kirsten X Jacobsen, Heather MacDonald, Sylvie Lemonde, Mireille Daigle, David A Grimes, Dennis E Bulman, Paul R Albert
(Affiliation: Ottawa Health Research Institute, Ottawa, Ontario, Canada.)
|
| Journal | Neurobiology of disease
(Neurobiol Dis)
Vol. 29
Issue 1
Pg. 117-22
(Jan 2008)
ISSN: 0969-9961 United States |
| PMID | 17890097
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- DNA-Binding Proteins
- Dopamine Agonists
- Enzyme Inhibitors
- Flavonoids
- Nurr1 nuclear receptor
- PD 98059
- Transcription Factors
- Cysteine
- Serine
- Quinpirole
- Tyrosine 3-Monooxygenase
- Mitogen-Activated Protein Kinase 3
|
| Topics |
- Cell Line, Transformed
- Cysteine
(genetics)
- DNA-Binding Proteins
(genetics)
- Dopamine Agonists
(pharmacology)
- Drug Interactions
- Enzyme Activation
(drug effects)
- Enzyme Inhibitors
(pharmacology)
- Flavonoids
(pharmacology)
- Gene Expression Regulation
(drug effects, genetics)
- Humans
- Mitogen-Activated Protein Kinase 3
(physiology)
- Mutation
(physiology)
- Neuroblastoma
(pathology)
- Quinpirole
(pharmacology)
- Serine
(genetics)
- Transcription Factors
(genetics)
- Transfection
(methods)
- Tyrosine 3-Monooxygenase
(metabolism)
|
