Elsevier

Neurobiology of Disease

Volume 27, Issue 2, August 2007, Pages 141-150
Neurobiology of Disease

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

https://doi.org/10.1016/j.nbd.2007.03.014Get rights and content

Abstract

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 [3H]-DA synaptosomal uptake and [125I]-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.

Section snippets

Generation of null DJ-1 mice

Mice deficient in DJ-1 protein were generated with an embryonic stem cell line from a library created with a gene trap targeting vector (Baygenomics, Davis, CA). These ES cell lines were modified with the random insertion of vector containing an En2 intron–exon splice acceptor followed by the βgeo gene (a fusion of beta-galactosidase and neomycin resistance genes). The ES cell line (XE726) was determined by its 5′RACE sequence to have the βgeo trap insertion located in the DJ-1 gene locus in

DJ-1 −/− characterization

DJ-1-deficient mice were generated using an ES cell line (XE726) further modified with the random insertion of construct containing an En2 intron–exon splice acceptor followed by the βgeo gene (Fig. 1A). Immunohistochemical observation revealed lack of DJ-1 immunoreactivity in genotypic null mice. In contrast, wild-type mice showed robust DJ-1 staining throughout the brain (Figs. 1B, C). The protein was present within neurons as well as non-neuronal cells with morphological features of

Discussion

Here we characterized a new line of transgenic mice deficient in DJ-1. Behavioral, neurochemical and pathological findings in these animals are similar to those previously reported in other DJ-1 knockout mice (Chen et al., 2005, Goldberg et al., 2005, Kim et al., 2005). In particular, we observed a slight deficit in locomotor behavior, which was not accompanied by a reduction in striatal DA and DA metabolites or a decrease in DAergic cell number in the substantia nigra. An important original

Acknowledgments

The authors thank Dr. Jennifer Tillerson for the assistance with behavioral assays and Arjun Raman for the IT-related assistance. This work was funded by the Michael J. Fox Foundation (A.B.M.-B.) and the NIH (National Institute of Environmental Health Sciences, ES 012077, J.W.L., D.A.D., A.B.M.-B.; ES 01268, G.W.M.; National Institute of Mental Health, Intramural Research Program, C.R.G.).

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