Pesticides and Parkinson's Disease

描述（由申请人提供）：虽然帕金森病（PD）的病因尚未明确，但流行病学研究表明，PD风险增加与职业暴露于杀虫剂（包括百草枯，一种广泛使用的除草剂）之间存在相关性。有趣的是，用百草枯治疗小鼠会产生PD的许多关键特征，包括大脑黑质致密部（SNpc）的多巴胺能神经元变性和含有1-突触核蛋白包涵体的形成。因此，对百草枯诱导的多巴胺能神经元死亡的研究可能为多巴胺能神经元的死亡和存活机制提供重要的新信息，从而为PD的分子基础提供重要的新见解。最近，我们发现百草枯选择性地杀死原代培养中的多巴胺能神经元，其机制需要激活c-Jun nh2末端蛋白激酶（JNK）和JNK诱导的基因表达。此外，百草枯诱导的多巴胺能神经元死亡可被bFGF抑制。这一建议是基于JNK，特别是神经特异性JNK3亚型在百草枯诱导的多巴胺能神经元死亡中起重要作用的假设，并且这种细胞死亡可能由BimEL介导，并被bFGF拮抗。这些机制研究将为帕金森氏症百草枯模型中多巴胺能神经元死亡的分子基础提供重要信息。此外，我们提出的研究符合NIEHS战略计划的目标，特别是目标2中的“支持研究，以提高我们对信号转导途径及其对疾病的影响的理解”，即“利用环境毒物了解人类生物学的基本机制”。帕金森病是第二常见的与衰老相关的神经退行性疾病。我们建议在体外和体内阐明百草枯诱导多巴胺能神经元死亡的分子机制。这些机制研究将为帕金森氏病百草枯模型中多巴胺能神经元死亡的分子基础提供重要信息，并可能为帕金森氏病的分子基础提供重要的新见解。

DESCRIPTION (provided by applicant): Although the etiology of Parkinson's disease (PD) has not been defined, epidemiological studies have indicated a correlation between increased risk for PD and occupational exposure to pesticides including paraquat, a widely used herbicide. Interestingly, treatment of mice with paraquat produces many key features of PD including dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc) of the brain and formation of 1-synuclein containing inclusion bodies. Therefore, studies of paraquat-induced dopaminergic neuron death may provide important new information concerning mechanisms governing the death and survival of dopaminergic neurons and thereby provide important new insights concerning the molecular basis of PD. Recently, we discovered that paraquat selectively kills dopaminergic neurons in primary cultures by a mechanism that requires activation of the c-Jun NH2-terminal protein kinase (JNK) and JNK-induced gene expression. Furthermore, paraquat-induced dopaminergic neuron death is inhibited by bFGF. This proposal is based upon the hypothesis that JNK, specifically the neurospecific JNK3 isoform, plays an important role in paraquat-induced death of dopaminergic neurons, and that this cell death may be mediated by BimEL and antagonized by bFGF. These mechanistic studies should provide critical information concerning the molecular basis of dopaminergic neuron death in the paraquat model of PD. Furthermore, our proposed research meets the goals of NIEHS strategic plan, especially to "support research that improves our understanding of signal transduction pathways and their influence on disease" under goal #2, which is to "use environmental toxicants to understand basic mechanisms in human biology". PUBLIC HEALTH RELEVANCE Parkinson's disease is the second most common aging-related neurodegenerative disorder. We propose to elucidate molecular mechanisms underlying paraquat-induced dopaminergic neuron death in vitro and in vivo. These mechanistic studies should provide critical information concerning the molecular basis of dopaminergic neuron death in the paraquat model of Parkinson's disease, and may provide important new insights concerning the molecular basis Parkinson's disease.