8-Oxoguanine, a major oxidized base lesion, has been inferred to be involved in the neurodegenerative diseases. To counteract oxidative damage to nucleic acids, MTH1 hydrolyzes oxidized purine nucleoside triphosphates, thus sanitizing nucleotide pools. OGG1, an 8-oxoguanine DNA glycosylase, prevents buildup of 8-oxoguanine in both nuclear and mitochondrial genomes. Our previous studies showed that MTH1-deficient young mice exhibited a greater accumulation of 8-oxoguanine after MPTP administration (Yamaguchi et al., Cell Death Differ, 2006). Aging is a risk factor for the development and progression of Parkinson's disease (PD), however, the mechanism by which 8-oxoguanine causes dopamine neurodegeneration in aged mice, has yet to be clarified.
In the present study, first, we observed that expression of MTH1 and OGG1 is abundantly detected in substantia nigra. Then, double-immunodetection with neuronal markers revealed that dopaminergic neurons co-express both MTH1 and OGG1. Furthermore, we show that the MPTP-treated mutant mice lacking MTH1 and OGG1 exhibit abnormal behavior compared to wild-type mice. These results strongly suggest that MTH1 and OGG1 contribute to the maintenance of genomic integrity in dopaminergic neurons, and play an important role in PD pathogenesis.