The Role of Mitochondrial DNA Damage in Neurodegeneration

描述（由申请人提供）：本研究的长期目标是阐明持续线粒体DNA损伤在神经变性中的作用。现在有强有力的证据表明，大多数帕金森病病例的神经退行性变是遗传差异与环境暴露（基因-环境相互作用）相互作用的结果，但所涉及的基因和环境暴露都没有得到很好的理解。我们正在研究一种新的假设，即一些重要的环境毒素通过引起持续的线粒体DNA损伤而导致神经退行性变，而处理这种损伤的过程中的遗传缺陷导致更大的易感性。线粒体DNA比核DNA对多种损伤更为敏感，但对于多环芳烃和紫外线等重要环境基因毒素造成的线粒体DNA损伤，目前尚无明显的修复途径。我们将测试这种损伤在关键发育时期暴露导致神经退行性变中的作用。这种效果的特异性将使用创新的新的转基因秀丽隐杆线虫菌株进行测试。我们还将利用秀丽隐杆线虫现有的遗传和分子工具，验证参与线粒体融合和自噬的特定基因保护免受这种损害的假设。现在有强有力的证据表明，大多数帕金森病病例的神经退行性变是遗传差异和环境暴露（基因-环境相互作用）共同作用的结果，但所涉及的基因和环境暴露都没有得到很好的理解。我们将验证这样一个假设：重要的、常见的环境毒素通过在脆弱的发育时期造成持续的线粒体DNA损伤而导致神经退行性变，而处理这种损伤的过程中的遗传缺陷导致更大的易感性。如果是这样的话，更好地控制这些化学物质可以大大减少帕金森病的发病率，也可能减少其他神经退行性疾病的发病率。

DESCRIPTION (provided by applicant): The long-range goal of this research is to elucidate the role of persistent mitochondrial DNA damage in neurodegeneration. There is now strong evidence that neurodegeneration in the majority of Parkinson's Disease cases is the result of the interplay of genetic differences with environmental exposures (gene-environment interactions), but neither the genes nor the environmental exposures involved are well understood. We are investigating the novel hypothesis that some important environmental toxins contribute to neurodegeneration by causing persistent mitochondrial DNA damage, and that genetic deficiencies in the processes that handle such damage lead to greater susceptibility. Mitochondrial DNA is more sensitive than nuclear DNA to many insults, and there is no apparent repair pathway for handling mitochondrial DNA damage caused by important environmental genotoxins such as polycyclic aromatic hydrocarbons and ultraviolet radiation. We will test the role of such damage in causing neurodegeneration as a result of exposure during key developmental time periods. The specificity of this effect will be tested using innovative new transgenic strains of Caenorhabditis elegans. We will also test the hypothesis that specific genes involved in mitochondrial fusion and autophagy protect against such damage, taking advantage of the genetic and molecular tools available in Caenorhabditis elegans. Description of relevance to public health There is now strong evidence that neurodegeneration in most Parkinson's Disease cases is the result of the combined effects of genetic differences and environmental exposures (gene- environment interactions), but neither the genes nor the environmental exposures involved are well understood. We will test the hypothesis that important, common environmental toxins contribute to neurodegeneration act by causing persistent mitochondrial DNA damage during vulnerable periods of development, and that genetic deficiencies in the processes that handle such damage lead to greater susceptibility. If this is the case, better regulation of such chemicals could greatly reduce the incidence of Parkinson's Disease, and possibly other neurodegenerative diseases as well. PUBLIC HEALTH RELEVANCE: There is now strong evidence that neurodegeneration in most Parkinson's Disease cases is the result of the combined effects of genetic differences and environmental exposures (gene- environment interactions), but neither the genes nor the environmental exposures involved are well understood. We will test the hypothesis that important, common environmental toxins contribute to neurodegeneration act by causing persistent mitochondrial DNA damage during vulnerable periods of development, and that genetic deficiencies in the processes that handle such damage lead to greater susceptibility. If this is the case, better regulation of such chemicals could greatly reduce the incidence of Parkinson's Disease, and possibly other neurodegenerative diseases as well.