Lack of the DNA repair enzyme OGG1 sensitizes dopamine neurons to manganese toxicity during development.
Onset of Parkinson's disease (PD) and Parkinson-like syndromes has been associated with exposure to diverse environmental stimuli. Epidemiological studies have demonstrated that exposure to elevated levels of manganese produces neuropathological changes localized to the basal ganglia, including neuronal loss and depletions in striatal dopamine content. However, understanding the mechanisms associated with manganese neurotoxicity has been hampered by the lack of a good rodent model. Elevated levels of 8-hydroxy-2'-deoxyguanosine (oxo8dG) have been found in brain areas affected in PD. Whether increased DNA damage is responsible for neuronal degeneration or is a mere epiphenomena of neuronal loss remains to be elucidated. Thus, by using mice deficient in the ability to remove oxo8dG we aimed to determine if dysregulation of DNA repair coupled to manganese exposure would be detrimental to dopaminergic neurons. Wild-type and OGG1 knockout mice were exposed to manganese from conception to postnatal day 30; in both groups, exposure to manganese led to alterations in the neurochemistry of the nigrostriatal system. After exposure, dopamine levels were elevated in the caudate of wild-type mice. Dopamine was reduced in the caudate of OGG1 knockout mice, a loss that was paralleled by an increase in the dopamine index of turnover. In addition, the reduction of dopamine in caudate putamen correlated with the accumulation of oxo8dG in midbrain. We conclude that OGG1 function is essential in maintaining neuronal stability during development and identify DNA damage as a common pathway in neuronal loss after a toxicological challenge.
Cardozo-Pelaez
Fernando
F
Centerfor Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA. fernando.cardozo@umontana.edu
Cox
David P
DP
Bolin
Celeste
C
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000254:growth & development; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D008345:Manganese / Q000633:toxicity*; D008636:Mesencephalon / Q000201:enzymology / Q000254:growth & development; D051379:Mice; D018345:Mice, Knockout; D017072:Neostriatum / Q000254:growth & development / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
D008345:Manganese; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D004298:Dopamine