Gene-Environment Interactions in Neurodegeneration: Role of Efflux Transporters

描述（由申请人提供）：帕金森病（PD）是一种慢性退行性神经系统疾病，估计在美国至少影响100万人，在全球范围内影响1000万人。PD是一种复杂的疾病，没有单一基因与显著百分比的病例相关，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。异生素转运蛋白多药耐药蛋白1（MDR 1，也称为P-糖蛋白）的多态性降低了其功能，在暴露于农药的PD患者中观察到的频率更高。这一发现增加了MDR 1功能改变增加暴露于农药的人患PD风险的可能性。由于MDR 1在从大脑中排出化学物质方面至关重要，我们假设MDR 1积极地从大脑中排出农药，并且这种转运蛋白的遗传或获得性缺陷可能导致神经退行性变。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，负责从大脑中清除农药，包括与多巴胺能神经变性有关的除草剂百草枯，并保护神经变性。这是重要的，因为1）MDR 1在人脑毛细血管内皮细胞和其他神经元细胞中显著表达，2）MDR 1的多态性与暴露于农药的患者中PD风险增加相关，以及3）与多种退行性疾病（包括PD）相关的神经炎症已被发现下调MDR 1。因此，预计这些数据将提供一个更好的理解MDR 1的遗传和炎症调节以及MDR 1在农药在大脑中的保留的潜在作用，并将使我们能够确定MDR 1，农药和神经退行性疾病之间的基因-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.