Which mechanisms of pollutant-induced mitochondrial dysfunction cause dopaminergic neurodegeneration?

帕金森氏症(PD)影响着1%到2%的60岁以上人口。多种治疗方法 费用高昂，虽然它们暂时缓解了症状，但目前没有一种方法可以减缓进展。 因此，了解帕金森病的机制基础对于预防和治疗都至关重要。 努力。环境因素是导致帕金森病的重要因素，实验室、临床和 流行病学研究已经证明了几种特定的化学品暴露所起的作用。所有这些都是 化学物质会影响线粒体。然而，有强有力的证据表明，只有少数人与帕金森病有关 化学物质，由于接触大量这些化学物质的人相对较少， 它们加在一起可能只解释了帕金森病的一小部分。最近的高通量毒物学筛查 已经证明，商业中即使不是数千种化学物质，也有数百种会导致线粒体 功能障碍和毒性。要彻底测试所有这些是不可能的，但监管行动需要 清除毒物学数据。我们如何才能合理地对这些化学物质进行测试？ 尽管这些化学物质都是有丝分裂毒物，但它们 有多种毒性机制。这些包括抑制所有四个电子链复合体，ATP 合酶和Krebs循环酶；氧化还原循环；线粒体DNA损伤；以及ATP解偶联 耗氧量所产生的产量。我们建议缩小努力的重点，以确定 可能导致帕金森病的化学物质，通过澄清许多机制中的哪些 导致“线粒体功能障碍”的化学物质会导致多巴胺能神经变性。 我们将确定哪些特定形式的线粒体功能障碍会导致多巴胺能 神经退行性变。我们还将测试关键的下游结果，氧化应激和三磷酸腺苷 耗竭，是多巴胺能神经退化所必需的。这层额外的机械性 了解有助于高通量筛查，并可能为治疗努力提供信息。 我们将通过使用污染物来测试特定形式的线粒体功能障碍的因果关系 不同的丝裂毒性机制；通过比较能量和氧化应激变化的时间线与 神经退化；以及通过抢救实验。为了检查如此大量的曝光量 在活体内，但严谨和高度复制的方式，我们将工作在模型生物线虫 优雅女装。我们正在开发新的线虫品系，这将使我们能够在 在同一个体中，对所有这些参数的细胞类型特定变化进行活体评估。 总体而言，这项工作的结果将有助于从机械上划定化学物质的景观。 可能导致帕金森病的暴露，指导监管指南的制定以及证明 未来在脊椎动物模型和流行病学研究方面的更多研究。

Parkinson’s disease (PD) affects one to two percent of the population over age 60. Many treatments are costly, and while they temporarily alleviate symptoms, none currently available slow progression. Therefore, understanding the mechanistic basis of PD is critical to inform both preventive and therapeutic efforts. Environmental factors are important contributors to PD, and laboratory, clinical, and epidemiological studies have demonstrated a role for several specific chemical exposures. All of these chemicals affect mitochondria. However, there is strong evidence for association with PD for only a few chemicals, and because relatively few people are exposed to significant amounts of those chemicals, they collectively likely explain only a small fraction of PD. Recent high-throughput toxicological screens have demonstrated that hundreds if not thousands of chemicals in commerce cause mitochondrial dysfunction and toxicity. It is not possible to test all of these thoroughly, and yet regulatory action requires clear toxicological data. How can we rationally prioritize these chemicals for testing? A way forward is suggested by the fact that although these chemicals are all mitotoxicants, they have multiple mechanisms of toxicity. These include inhibition of all four electron chain complexes, ATP synthase, and Krebs cycle enzymes; redox cycling; mitochondrial DNA damage; and uncoupling of ATP production from oxygen consumption. We propose to narrow the focus of efforts to identify chemicals that could contribute to PD, by clarifying which of the many mechanisms by which chemicals cause “mitochondrial dysfunction” can contribute to dopaminergic neurodegeneration. We will define which specific forms of mitochondrial dysfunction result in dopaminergic neurodegeneration. We will also test whether key downstream outcomes, oxidative stress and ATP depletion, are required for dopaminergic neurodegeneration. This additional layer of mechanistic understanding lends itself to high-throughput screening, and may be informative for therapeutic efforts. We will test the causality of specific forms of mitochondrial dysfunction by using pollutants that act by different mitotoxic mechanisms; by comparing the timeline of energetic and oxidative stress changes with neurodegeneration; and by rescue experiments. In order to examine this large number of exposures in an in vivo, yet rigorous and highly replicated fashion, we will work in the model organism Caenorhabditis elegans. We are developing novel strains of C. elegans that will permit us to carry out aging-related, in vivo assessments of cell type-specific changes to all of these parameters, in the same individuals. Overall, results from this work will serve to mechanistically delimit the landscape of chemical exposures that could contribute to PD, guiding regulatory guideline development as well as justifying additional future research in vertebrate models and epidemiological studies.