A Nurr1 point mutant, implicated in Parkinson's disease, uncouples ERK1/2-dependent regulation of tyrosine hydroxylase transcription

Neurobiol Dis. 2008 Jan;29(1):117-22. doi: 10.1016/j.nbd.2007.08.003. Epub 2007 Aug 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Gene Expression Regulation / genetics*
  • Humans
  • Mitogen-Activated Protein Kinase 3 / physiology*
  • Mutation / physiology*
  • Neuroblastoma / pathology
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Quinpirole / pharmacology
  • Serine / genetics
  • Transcription Factors / genetics*
  • Transfection / methods
  • Tyrosine 3-Monooxygenase / metabolism*


  • DNA-Binding Proteins
  • Dopamine Agonists
  • Enzyme Inhibitors
  • Flavonoids
  • NR4A2 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Transcription Factors
  • Quinpirole
  • Serine
  • Tyrosine 3-Monooxygenase
  • Mitogen-Activated Protein Kinase 3
  • Cysteine
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one