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.

帕金森病（PD）影响60岁以上人口的1%至2%。许多治疗方法 虽然它们可以暂时缓解症状，但目前没有一种可以减缓病情进展。 因此，了解PD的机制基础对于预防和治疗至关重要 努力环境因素是PD的重要因素，实验室、临床和 流行病学研究表明，若干特定的化学品接触会产生影响。所有这些 化学物质影响线粒体。然而，有强有力的证据表明，只有少数人与PD有关。 化学品，因为相对较少的人接触到大量的这些化学品， 它们加在一起可能只能解释PD的一小部分。最近的高通量毒理学筛选 已经证明，如果不是成千上万的商业化学品， 功能障碍和毒性。不可能彻底测试所有这些，但监管行动需要 明确的毒理学数据。我们如何合理地优先考虑这些化学品进行测试？ 尽管这些化学物质都是有丝分裂毒素， 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 合成酶和克雷布斯循环酶;氧化还原循环;线粒体DNA损伤; ATP解偶联 从氧气消耗中生产。我们建议缩小工作重点， 化学品，可以有助于PD，通过澄清的许多机制， 引起“线粒体功能障碍”的化学物质可能导致多巴胺能神经变性。 我们将定义哪些特定形式的线粒体功能障碍导致多巴胺能神经递质的减少。 神经变性我们还将测试关键的下游结果，氧化应激和ATP 消耗，是多巴胺能神经变性所必需的。这种额外的机械层 了解有助于高通量筛选，并可能为治疗工作提供信息。 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， 不同的有丝分裂毒性机制;通过比较能量和氧化应激变化的时间轴， 神经变性;和通过拯救实验。为了检查大量的曝光， 在体内，但严格和高度复制的方式，我们将在模式生物小杆线虫 优雅的我们正在开发新的C菌株。这将使我们能够进行与衰老有关的， 在相同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划定化学景观 可能导致PD的暴露，指导监管指南的制定以及证明 今后还将开展脊椎动物模型和流行病学研究。