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. 2005;12(4-6):315-23.
doi: 10.3727/000000005783992007.

Lack of the DNA repair enzyme OGG1 sensitizes dopamine neurons to manganese toxicity during development

Fernando Cardozo-Pelaez  1 , David P Cox, Celeste Bolin
Affiliations

Lack of the DNA repair enzyme OGG1 sensitizes dopamine neurons to manganese toxicity during development

Fernando Cardozo-Pelaez et al. Gene Expr. 2005.

Abstract

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.

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Figures

Figure 1
Figure 1
Gel for analysis of OGG1 activity in midbrain of wild-type (+/+) and OGG1 knockout (−/−) mice. Activity of OGG1 enzyme yielded two bands: top band is intact 32P-labeled oligonucleotide, lower band is the 32P-labeled oligonucleotide cleaved by OGG1 and separated by electrophoresis. Lane 1: negative control (no enzyme), lane 2: positive control (Fpg glycosylase enzyme), lane 3: activity in midbrain of wild-type (+/+) mouse, lane 4: activity in midbrain of OGG1 knockout (−/−) mouse.
Figure 2
Figure 2
Levels of dopamine, DOPAC, and HVA in caudate putamen of young mice (PND 30) exposed to manganese throughout development. Data expressed as micrograms of dopamine per weight of wet tissue (mean ± SEM). *Significant difference from control (p < 0.05; n = 7–10).
Figure 3
Figure 3
Index of turnover for dopamine in nerve terminals of the nigrostriatal pathway of OGG1 knockout mice. Index of turnover defined as (DOPAC + HVA)/dopamine levels. Data presented as mean ± SEM. *Significant difference from control (p < 0.05; n = 7–10).
Figure 4
Figure 4
Dopamine levels in caudate putamen in relationship to oxo8dG levels in midbrain. Linear regression analysis indicates that an inverse relationship does exist. Pearson’s correlation analysis (p < 0.05).
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References

    1. Arai T.; et al. High accumulation of oxidative DNA damage, 8-hydroxyguanine, in Mmh/Ogg1 deficient mice by chronic oxidative stress. Carcinogenesis 23(12):2005–2010; 2002. - PubMed
    1. Bernheimer H.; et al. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J. Neurol. Sci. 20(4):415–455; 1973. - PubMed
    1. Bogdanov M.; et al. Increased oxidative damage to DNA in ALS patients. Free Radic. Biol. Med. 29(7):652–658; 2000. - PubMed
    1. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72:248–254; 1976. - PubMed
    1. Brenneman K. A.; et al. Manganese-induced developmental neurotoxicity in the CD rat: Is oxidative damage a mechanism of action? Neurotoxicology 20(2–3): 477–487; 1999. - PubMed

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