Gene-Environment Interactions in Neurodegeneration: Role of Efflux Transporters

帕金森病（PD）是一种慢性退行性神经系统疾病，估计至少影响1 美国有1000万人，全球有1000多万人。帕金森病是一种复杂的疾病，没有一个基因 与相当比例的病例有关，这表明环境因素或基因-环境 相互作用可能导致病因或临床表现。异生物质的多态性 转运蛋白多药耐药蛋白1（MDR 1，也称为P-糖蛋白）降低其功能， 在暴露于农药的PD患者中更常见。这一发现提高了 MDR 1功能改变可能会增加暴露于农药的人患PD的风险。由于MDR 1是 在从大脑中排出化学物质方面至关重要，我们假设MDR 1主动流出 杀虫剂从大脑和遗传或后天缺乏这种转运可能有助于 神经变性我们的主要研究目的是确定MDR 1作为主要的外排转运蛋白， 去除杀虫剂，包括与多巴胺能神经生成有关的除草剂百草枯， 防止神经退化这一点很重要，因为1）MDR 1显著 在人脑毛细血管内皮细胞和其他神经元细胞中表达，2）MDR 1的多态性 与暴露于农药的患者PD风险增加有关，3）神经炎症， 与包括PD在内的多种退行性疾病相关，已发现其下调MDR 1。 因此，预计这些数据将提供对遗传和炎症的更好理解。 MDR 1的调节以及MDR 1在农药在大脑中的保留中的潜在作用，并将 使我们能够确定MDR 1，农药和 神经变性

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 over 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.