Pathogenic Mechanisms of Environmental Toxicants in Parkinson's Disease

环境毒物对帕金森病的致病机制

• 批准号: 7616565
• 负责人: LIAN LI
• 金额: $ 34.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616565
• 关键词: Accounting; Animals; Behavioral; Biochemical; Biological; Brain; Brain region; Cell Survival; Cells; Cultured Cells; Data; Dieldrin; Disease; Environment; Environmental Risk Factor; Epidemiologic Studies; Etiology; Exposure to; Gene Mutation; Genes; Genetic; Goals; Human; Inherited; Knock-out; Lead; Link; Mediating; Modeling; Modification; Molecular; Molecular Genetics; Movement Disorders; Mutant Strains Mice; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Oxidation-Reduction; Oxidative Stress; Paper; Paraquat; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Pesticides; Phenotype; Play; Predisposition; Proteins; Proteomics; Publishing; Reactive Oxygen Species; Research; Risk; Risk Factors; Role; Rotenone; Series; Site; Site-Directed Mutagenesis; Structure; Substantia nigra structure; Testing; Toxic Environmental Substances; Transgenic Mice; animal model development; dopaminergic neuron; early onset; effective therapy; gene environment interaction; in vivo; insight; meetings; mouse model; mutant; neuron loss; nigrostriatal system; novel; oxidation; oxidative damage; prevent; public health relevance; toxicant

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the most common neurodegenerative movement disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra. The etiology of PD remains unknown. Epidemiological studies have revealed that exposure to environmental toxicants, including pesticides, increases the risk of PD. Many of these toxicants, such as rotenone, paraquat, and 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), have been shown to increase the levels of reactive oxygen species (ROS) and cause PD-like phenotypes in animals. These and other lines of evidence have implicated a crucial role for oxidative stress in PD pathogenesis. However, it is not known how environmental toxicant-induced oxidative stress leads to neuronal dysfunction and, ultimately, neuronal cell death. The long-term goal of this research is to elucidate the molecular mechanisms by which environmental toxicants cause neurodegeneration in PD. While only a very small percentage of PD cases are monogenic familial forms, molecular characterization of the identified familial PD proteins has revealed novel pathways involved in PD pathogenesis. DJ-1 is a recently identified PD gene whose mutations cause an early-onset, autosomal recessive form of familial PD. Accumulating evidence indicates that DJ-1 plays an essential role in protecting dopaminergic neurons against oxidative stress. This project will investigate the interaction between the familial PD gene DJ-1 and sporadic PD-associated environmental toxicants, and test the hypothesis that environmental toxicants cause oxidative damage to DJ-1, thereby contributing to the pathogenesis of sporadic PD in a manner similar to DJ-1 genetic mutations in causing familial PD. A combination of biochemical, proteomic, biophysical, cell biological, and molecular genetic approaches will be used to characterize the environmental toxicant-induced oxidative damage to DJ-1, examine the in vivo role of environmental toxicant-induced DJ-1 oxidation in PD pathogenesis, and determine the mechanisms by which environmental toxicants disrupt the DJ-1 neuroprotective pathway. Completion of this project should advance our understanding of the mechanistic role of environmental toxicants in neurodegeneration and help develop more effective therapies to treat PD. PUBLIC HEALTH RELEVANCE Project Narrative Although the etiology of Parkinson's disease (PD) remains unknown, there is compelling evidence that environmental toxicants, especially pesticides, are dominant risk factors in sporadic PD. The goal of the proposed research is to determine how environmental toxicants lead to neuronal dysfunction and, ultimately, neuronal cell death in PD. The results of the proposed studies will promote the discovery of new therapies for preventing and treating this devastating illness.

描述（由申请人提供）：帕金森病（PD）是最常见的神经退行性运动障碍，其特征为黑质多巴胺能神经元的进行性变性。PD的病因仍然未知。流行病学研究表明，暴露于环境毒物，包括农药，增加PD的风险。许多这些毒物，如鱼藤酮，百草枯和1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP），已被证明会增加活性氧（ROS）的水平，并导致PD样表型的动物。这些和其他证据表明，氧化应激在PD发病机制中起着至关重要的作用。然而，目前尚不清楚环境毒物诱导的氧化应激如何导致神经元功能障碍，并最终导致神经元细胞死亡。本研究的长期目标是阐明环境毒物引起PD神经退行性变的分子机制。虽然只有很小比例的PD病例是单基因家族形式，但已鉴定的家族性PD蛋白的分子表征揭示了参与PD发病机制的新途径。DJ-1是最近发现的PD基因，其突变导致家族性PD的早发性、常染色体隐性形式。越来越多的证据表明，DJ-1在保护多巴胺能神经元免受氧化应激中起着重要作用。本项目将研究家族性PD基因DJ-1与散发性PD相关环境毒物之间的相互作用，并验证环境毒物对DJ-1造成氧化损伤，从而以类似于DJ-1基因突变导致家族性PD的方式促进散发性PD发病的假设。生物化学，蛋白质组学，生物物理学，细胞生物学和分子遗传学方法的组合将被用来表征环境毒物诱导的DJ-1氧化损伤，检查在体内的作用，环境毒物诱导的DJ-1氧化PD发病机制，并确定环境毒物破坏DJ-1神经保护通路的机制。这个项目的完成将促进我们对环境毒物在神经退行性变中的机制作用的理解，并有助于开发更有效的治疗PD的方法。虽然帕金森病（PD）的病因仍然未知，但有令人信服的证据表明，环境毒物，特别是农药，是散发性PD的主要危险因素。这项研究的目的是确定环境毒物如何导致PD中的神经元功能障碍，并最终导致神经元细胞死亡。拟议研究的结果将促进发现预防和治疗这种毁灭性疾病的新疗法。