Mesencephalic and striatal protein profiles in mice over-expressing glucose-6-phosphate dehydrogenase in dopaminergic neurons.

Oxidative damage in dopaminergic neurons of the substantia nigra plays an important role in the pathogenesis of Parkinson's disease. Glucose-6-phosphate dehydrogenase (G6PD) is a key protective enzyme responsible for maintaining adequate levels of the major cellular reducing agent NADPH. We have previously shown that over-expression of G6PD in dopaminergic neurons of the substantia nigra results in resistance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in mice. In order to further examine this neuroprotective effect, a comparative proteomic study of the ventral mesencephalon (containing substantia nigra) and the striatum between wild-type and G6PD over-expressing mice was carried out. In addition to the protein level, over-expression of G6PD in the transgenic animals was also confirmed by determination of mRNA and enzymatic activity. Proteins with differential expression were mainly involved in antioxidant defense, detoxification and synaptic function, as demonstrated by gene ontology analysis. Hence, the changes in the nigrostriatal protein profile could partially explain the protection against MPTP-induced neuronal damage, and could also lead to new potential targets for antioxidant pharmacological intervention.