Lack of the DNA repair enzyme OGG1 sensitizes dopamine neurons to manganese toxicity during development
Lack of the DNA repair enzyme OGG1 sensitizes dopamine neurons to manganese toxicity during development
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DOI：
10.3727/000000005783992007
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
Bolin, C
中科院分区：
文献类型：
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作者：
Cardozo-Pelaez, F;Cox, DP;Bolin, C
帕金森病（PD）和帕金森样综合征的发病与暴露于不同的环境刺激有关。流行病学研究表明，暴露于高水平的锰会产生局限于基底神经节的神经病理学变化，包括神经元损失和纹状体多巴胺含量的耗竭。然而，由于缺乏良好的啮齿动物模型，理解与锰神经毒性相关的机制受到阻碍。在受PD影响的脑区发现8-羟基-2 '-脱氧鸟苷（oxo（8）dG）水平升高。DNA损伤的增加是否是神经元变性的原因，或者仅仅是神经元丢失的附带现象，仍有待阐明。因此，通过使用缺乏清除oxo（8）dG能力的小鼠，我们旨在确定与锰暴露相关的DNA修复失调是否对多巴胺能神经元有害。野生型和OGG 1基因敲除小鼠从受孕到出生后第30天暴露于锰;在这两组中，暴露于锰导致黑质纹状体系统的神经化学改变。暴露后，野生型小鼠尾状核中的多巴胺水平升高。多巴胺在OGG 1基因敲除小鼠的尾状核中减少，这种损失被多巴胺周转指数的增加所抵消。此外，尾壳核中多巴胺的减少与中脑中oxo（8）dG的积累相关。我们的结论是，OGG 1功能是必不可少的，在发展过程中维持神经元的稳定性，并确定DNA损伤作为一个共同的途径，在神经元的损失后，毒理学的挑战。
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 (oxo(8)dG) 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 oxo(8)dG 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 oxo(8)dG 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.