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

污染物引起的线粒体功能障碍的哪些机制导致多巴胺能神经变性？

• 批准号: 10606235
• 负责人: Joel Newman Meyer
• 金额: $ 41.79万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606235
• 关键词: Affect; Age; Aging; Caenorhabditis elegans; Cells; Chemical Actions; Chemical Exposure; Chemicals; Citric Acid Cycle; Clinical Research; Commerce; Complement; Complex; Consumption; DNA Damage; Data; Development; Electrons; Environment; Environmental Pollutants; Environmental Risk Factor; Enzyme Inhibition; Enzymes; Etiology; Event; Exposure to; Genetic; Guidelines; Idiopathic Parkinson Disease; Incidence; Individual; Laboratory Study; Longevity; Measurement; Measures; Mediating; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Multienzyme Complexes; Nature; Nerve Degeneration; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen Consumption; Parkinson Disease; Pathway interactions; Persons; Pharmaceutical Preparations; Pollution; Population; Preventive; Production; Publishing; Reactive Oxygen Species; Reporter Genes; Research; Role; Stress; Testing; Therapeutic; Time; Toxic effect; Toxicology; Transgenic Organisms; Treatment Cost; Work; adverse outcome; alpha synuclein; cell type; cholinergic neuron; cost; disorder risk; dopaminergic neuron; epidemiology study; experimental study; high throughput screening; in vivo; insight; mitochondrial dysfunction; model organism; neurotoxicity; novel; pollutant; reduce symptoms; timeline; tool

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.

帕金森氏病（PD）影响60岁以上的人口的一到百分之二。许多治疗方法 昂贵，虽然它们暂时缓解症状，但目前没有一个可用的缓慢进展。 因此，了解PD的机理基础对于告知预防和治疗至关重要 努力。环境因素是PD，实验室，临床和 流行病学研究表明，几种特定化学暴露的作用。所有这些 化学物质会影响线粒体。但是，只有少数几个 化学药品，并且由于相对较少的人暴露于大量化学物质，所以 他们共同解释了PD的一小部分。最近的高通量毒理学屏幕 已经证明了数百种甚至数千种商业中的化学物质会导致线粒体 功能障碍和毒性。不可能诚实地测试所有这些，但监管行动需要 清晰的毒理学数据。我们如何合理地将这些化学品优先考虑测试？ 尽管这些化学物质都是有丝毒剂，但它们都提出了前进的道路 具有多种毒性机制。这些包括抑制所有四个电子链复合物ATP 合酶和克雷布斯循环酶；氧化还原循环；线粒体DNA损伤；和ATP的解偶联 消耗氧气的生产。我们建议缩小确定努力的重点 通过确定哪种机制中的哪种化学物质可以导致PD 化学物质引起“线粒体功能障碍”会导致多巴胺能神经变性。 我们将定义哪种特定形式的线粒体功能障碍会导致多巴胺能 神经变性。我们还将测试关键下游结果，氧化应激和ATP是否 多巴胺能神经退行性的耗竭是必需的。额外的机械层 理解可以进行高通量筛查，并可能为治疗努力提供信息。 我们将通过使用由作用的污染物来测试特定形式的线粒体功能障碍的因果关系 不同的有丝毒机制；通过比较能量的时间表和氧化应激随着 神经变性；并通过救援实验。为了检查大量的暴露 在体内，但严格而高度复制的时尚，我们将在模型有机体中工作 秀丽隐杆线。我们正在开发新颖的秀丽隐杆线虫菌株，这将使我们能够进行与衰老有关的菌株 在同一个体中，对所有这些参数的细胞类型特异性变化的体内评估。 总体而言，这项工作的结果将有助于机械地界定化学景观 可能有助于PD的暴露，指导监管指南开发以及证明是合理的 在脊椎动物模型和流行病学研究中的其他未来研究。