Gene-Environment Interactions in Neurodegeneration: Role of Efflux Transporters

描述(申请人提供)：帕金森氏病(PD)是一种慢性退行性神经疾病，估计在美国至少有100万人受到影响，全球有1000万人。帕金森病是一种复杂的疾病，没有单个基因与很大比例的病例有关，这表明环境因素或基因-环境相互作用可能有助于病因或临床表现。异种转运体多药耐药蛋白1(MDR1，又称P-糖蛋白)基因多态性降低了其功能，在接触杀虫剂的PD患者中更频繁地被观察到。这一发现增加了这样一种可能性，即mdr1功能改变会增加接触杀虫剂的人患帕金森病的风险。由于mdr1在从大脑中排出化学物质方面至关重要，我们假设mdr1主动将杀虫剂从大脑中排出，这种转运蛋白的遗传或后天缺陷可能导致神经退化。我们的主要研究目的是确定MDR1是一种主要的外排转运体，负责从大脑中清除杀虫剂，包括与多巴胺能神经生成有关的除草剂百草枯，并防止神经退化。这是因为1)mdr1在人脑毛细血管内皮细胞和其他神经细胞中显著表达，2)mdr1基因多态与接触杀虫剂的患者患帕金森病的风险增加有关，3)与包括帕金森病在内的多种退行性疾病相关的神经炎症已被发现下调mdr1基因。因此，这些数据有望更好地了解MDR1的遗传和炎症调节以及MDR1在农药在脑内滞留中的潜在作用，并将使我们能够确定MDR1、农药和神经退行性变之间的基因-环境相互作用的机制。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a chronic, degenerative neurological disorder that is estimated to affect at least 1 million individuals in the U.S. and ovr 10 million worldwide. PD is a complex disorder, and no single gene has been linked to a significant percentage of cases, suggesting that environmental factors or gene-environment interactions may contribute to the etiology or clinical manifestation. A polymorphism in the xenobiotic transporter Multidrug resistance protein 1 (MDR1, also known as P-glycoprotein) that reduces its function has been observed more frequently in PD patients who were exposed to pesticides. This finding raises the possibility that altered MDR1 function increases the risk for PD in people exposed to pesticides. Since MDR1 is critically important in expelling chemicals from the brain, we have hypothesized that MDR1 actively effluxes pesticides from the brain and genetic or acquired deficiency in this transporter may contribute to neurodegeneration. Our main research aim is to identify MDR1 as a primary efflux transporter responsible for removing pesticides, including the herbicide paraquat that has been linked to dopaminergic neurodgeneration, from the brain and protecting against neurodegeneration. This is significant because 1) MDR1 is prominently expressed in human brain capillary endothelial cells and other neuronal cells, 2) a polymorphism in MDR1 has been associated with increased risk of PD in patients exposed to pesticides, and 3) neuroinflammation, which is associated with multiple degenerative diseases including PD, has been found to down-regulate MDR1. Therefore, it is expected that these data will provide a better understanding of the genetic and inflammatory regulation of MDR1 as well as the potential role of MDR1 in the retention of pesticides in the brain, and will allow us to determine the mechanism of gene-environment interactions between MDR1, pesticides, and neurodegeneration.