Pathogenic Mechanisms of Environmental Toxicants in Parkinson's Disease

描述（申请人提供）：帕金森病（PD）是最常见的神经退行性运动障碍，其特征是黑质多巴胺能神经元进行性变性。PD的病因尚不清楚。流行病学研究表明，接触环境毒物，包括杀虫剂，会增加患PD的风险。许多有毒物质，如鱼烯酮、百草枯和1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），已被证明会增加动物体内活性氧（ROS）的水平，并导致pd样表型。这些和其他证据暗示了氧化应激在帕金森病发病机制中的关键作用。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。虽然只有非常小比例的PD病例是单基因家族形式，但已鉴定的家族性PD蛋白的分子特征揭示了参与PD发病机制的新途径。DJ-1是最近发现的PD基因，其突变可导致家族性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方面起着至关重要的作用。本项目将研究家族性PD基因DJ-1与散发性PD相关的环境毒物之间的相互作用，验证环境毒物对DJ-1造成氧化损伤的假设，从而以类似于DJ-1基因突变导致家族性PD的方式参与散发性PD的发病机制。结合生物化学、蛋白质组学、生物物理学、细胞生物学和分子遗传学的方法来描述环境毒物诱导的DJ-1氧化损伤，研究环境毒物诱导的DJ-1氧化在PD发病机制中的体内作用，并确定环境毒物破坏DJ-1神经保护通路的机制。该项目的完成将促进我们对环境毒物在神经变性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。尽管帕金森病（PD）的病因尚不清楚，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。本研究的目的是确定环境毒物如何导致PD患者的神经元功能障碍，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。

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.