PT - JOURNAL ARTICLE AU - David N Hauser AU - Christopher T Primiani AU - Rebekah G Langston AU - Ravindran Kumaran AU - Mark R Cookson TI - “The Polg mutator phenotype does not cause dopaminergic neurodegeneration in DJ-1 deficient mice” AID - 10.1523/ENEURO.0075-14.2015 DP - 2015 Feb 24 TA - eneuro PG - ENEURO.0075-14.2015 4099 - http://www.eneuro.org/content/early/2015/02/24/ENEURO.0075-14.2015.short 4100 - http://www.eneuro.org/content/early/2015/02/24/ENEURO.0075-14.2015.full AB - Mutations in the DJ-1 gene cause autosomal recessive parkinsonism in humans. Several mouse models of DJ-1 deficiency have been developed, but they do not have dopaminergic neuron cell death in the substantia nigra pars compacta (SNpc). Mitochondrial DNA (mtDNA) damage occurs frequently in the aged human SNpc but not in the mouse SNpc. We hypothesized that the reason DJ-1 deficient mice do not have dopaminergic cell death is due to an absence of mtDNA damage. We tested this hypothesis by crossing DJ-1 deficient mice with mice that have similar amounts of mtDNA damage in their SNpc as aged humans (Polg mutator mice). At one year of age, we counted the amount of SNpc dopaminergic neurons in the mouse brains using both colorimetric and fluorescent staining followed by unbiased stereology. No evidence of dopaminergic cell death was observed in DJ-1 deficient mice with the Polg mutator mutation. Furthermore, we did not observe any difference in dopaminergic terminal immunostaining in the striatum of these mice. Finally, we did not observe any changes in the amount of GFAP positive astrocytes in the SNpc of these mice, indicative of a lack of astrogliosis. Altogether, our findings demonstrate the DJ-1 deficient mice, Polg mutator mice, and DJ-1 deficient Polg mutator mice have intact nigrastriatal pathways. Thus, the lack of mtDNA damage in the mouse SNpc does not underlie the absence of dopaminergic cell death in DJ-1 deficient mice. Significance Statement: Parkinson’s disease research has been hampered by the absence of animal models that replicate the disease phenotypes observed in humans. We hypothesized that the reason mice lacking DJ-1, a gene that causes parkinsonism when mutated, do not replicate the human phenotype is because mice do not have the same levels of mtDNA damage that humans do. We tested this hypothesis by crossing DJ-1 deficient mice with mice that develop similar amounts of mtDNA damage as humans. We found that the added stress of mtDNA damage does not cause the DJ-1 deficient mice to replicate the human phenotype. These data should be informative for the development of future animal models of Parkinson’s disease.