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.