Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter.

Mutations in the gene for DJ-1 have been associated with early-onset autosomal recessive parkinsonism. Previous studies of null DJ-1 mice have shown alterations in striatal dopamine (DA) transmission with no DAergic cell loss. Here we characterize a new line of DJ-1-deficient mice. A subtle locomotor deficit was present in the absence of a change in striatal DA levels. However, increased [(3)H]-DA synaptosomal uptake and [(125)I]-RTI-121 binding were measured in null DJ-1 vs. wild-type mice. Western analyses of synaptosomes revealed significantly higher dopamine transporter (DAT) levels in pre-synaptic membrane fractions. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure exacerbated striatal DA depletion in null DJ-1 mice with no difference in DAergic nigral cell loss. Furthermore, increased 1-methyl-4-phenylpyridinium (MPP(+)) synaptosomal uptake and enhanced MPP(+) accumulation were measured in DJ-1-deficient vs. control striatum. Thus, under null DJ-1 conditions, DAT changes likely contribute to altered DA neurotransmission and enhanced sensitivity to toxins that utilize DAT for nigrostriatal entry.