Reduced Nurr1 expression increases the vulnerability of mesencephalic dopamine neurons to MPTP-induced injury.
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.
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Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
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D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D002452:Cell Count; D003342:Corpus Striatum / Q000737:chemistry; D004268:DNA-Binding Proteins; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D005260:Female; D008297:Male; D008636:Mesencephalon / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D013378:Substantia Nigra / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D004268:DNA-Binding Proteins; D015259:Dopamine Agents; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine