Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injury

J Neurochem. 1999 Nov;73(5):2218-21.


Mutation in the Nurr1 gene, a member of the nuclear receptor superfamily, causes selective agenesis of dopaminergic neurons in the midbrain of null mice. Homozygous Nurr1 knockout mice (Nurr1-/-) die 1 day after birth, but heterozygous mice (Nurr1 +/-) survive postnatally without obvious locomotor deficits. Although adult Nurr1 +/- mice show significantly reduced Nurr1 protein levels in the substantia nigra (SN), they display a normal range of tyrosine hydroxylase-positive neuron numbers in the SN and normal levels of dopamine in the striatum. The reduction in Nurr1 expression in Nurr1 +/- mice, however, confers increased vulnerability to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) compared with wild-type (Nurr1 +/+) mice. This study suggests that Nurr1 may play an important role in maintaining mature mesencephalic dopaminergic neuron function and that a defect in Nurr1 may increase susceptibility to SN injury.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology*
  • Animals
  • Cell Count
  • Corpus Striatum / chemistry
  • DNA-Binding Proteins*
  • Dopamine / analysis
  • Dopamine / metabolism*
  • Dopamine Agents / pharmacology
  • Female
  • Male
  • Mesencephalon / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / drug effects*
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Substantia Nigra / cytology
  • Substantia Nigra / enzymology
  • Substantia Nigra / metabolism
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • Tyrosine 3-Monooxygenase / analysis


  • DNA-Binding Proteins
  • Dopamine Agents
  • Nr4a2 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • Transcription Factors
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Tyrosine 3-Monooxygenase
  • Dopamine