A Nurr1 point mutant, implicated in Parkinson's disease, uncouples ERK1/2-dependent regulation of tyrosine hydroxylase transcription.
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.
Jacobsen
Kirsten X
KX
Ottawa Health Research Institute, Ottawa, Ontario, Canada.
MacDonald
Heather
H
Lemonde
Sylvie
S
Daigle
Mireille
M
Grimes
David A
DA
Bulman
Dennis E
DE
Albert
Paul R
PR
D002461:Cell Line, Transformed; D003545:Cysteine / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D018491:Dopamine Agonists / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D009154:Mutation / Q000502:physiology*; D009447:Neuroblastoma / Q000473:pathology; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D019257:Quinpirole / Q000494:pharmacology; D012694:Serine / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection / Q000379:methods; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D005419:Flavonoids; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D019257:Quinpirole; D012694:Serine; D014446:Tyrosine 3-Monooxygenase; D048052:Mitogen-Activated Protein Kinase 3; D003545:Cysteine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one