Pesticide-Mediated Generation of a Toxic Neurotransmitter Metabolite

农药介导的有毒神经递质代谢物的产生

基本信息

批准号：
10288070
负责人：
JONATHAN A DOORN
金额：
$ 30.9万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288070
关键词：
Actins Address Adhesions Affect Age Agriculture Aldehydes Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Alzheimer&apos s neuropathogenesis Animal Model Antioxidants Area Asparagine Brain Brain region Cadherins Cell physiology Cells Cellular Metabolic Process Chemicals Chlorinated Hydrocarbons Cleaved cell Complex Development Dieldrin Disease Disease Progression Dopamine Dose Environmental Risk Factor Epidemiology Etiology Exposure to Extracellular Matrix Funding Generations Genetic Variation Goals Homeostasis Impairment Individual Injury Integrins Link Measurement Mechanoreceptors Mediating Metabolic Metabolic Biotransformation Metabolism Modeling Molecular Molecular Target Monoamine Oxidase Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Neurotransmitters Norepinephrine Outcome Oxidative Stress Parkinson Disease Pathologic Pathology Pathway interactions Peptide Hydrolases Pesticides Process Production Proteins Reaction Reporting Research Risk Role Signal Transduction Site Solid System Testing Tissues Translating Work cell injury detoxication disease diagnosis dopaminergic neuron early detection biomarkers elastography environmental agent exposed human population fluid flow gene environment interaction improved innovation locus ceruleus structure mechanical properties nerve supply nervous system disorder neuropathology neurotoxic neurotransmitter metabolism neurotransmitter release new therapeutic target noradrenergic novel pesticide exposure pesticide interaction phenylacetaldehyde polymerization potential biomarker response stem synergism tau Proteins tau aggregation toxicant trafficking viscoelasticity

项目摘要

PROJECT SUMMARY. Exposure to the organochlorine dieldrin predisposes individuals to Parkinson's Disease (PD); however, the mechanisms linking exposure to disease unknown. Dieldrin can disrupt DA homeostasis but alone may be insufficient for loss of dopamine (DA) neurons, and neurodegeneration may require an additional “hit”. Several animal models have demonstrated that altering DA homeostasis, metabolism and/or trafficking, yields progressive loss of DA neurons; therefore, a genetic variation modifying DA metabolism may be an additional “hit” that has toxic synergy with pesticide exposure. Disruption of DA homeostasis generates toxic intermediates such as ROS and aldehydes (3,4-dihydroxyphenylacetaldehyde, DOPAL), via monoamine oxidase. Similar to PD, there is evidence that dieldrin is a risk factor for Alzheimer's Disease (AD). It has been proposed that altered NE homeostasis is linked to the production of toxic species and cell injury relevant to AD. As with DA, NE is biotransformed via monoamine oxidase to an aldehyde (3,4- dihydroxyphenylglycolaldehyde, DOPEGAL), which is highly protein reactive and toxic. Early AD neuropathology occurs in the locus coeruleus (LC), a major site of NE innervation in the brain, and involves neurofibrillary tangles of the protein Tau, following its cleavage by an asparagine proteinase (AEP). Recent reports demonstrated that the NE metabolite, DOPEGAL, activates AEP to cleave Tau and induce Tau aggregation. Modulation of the extracellular matrix (ECM) is thought to be important for AD pathology and may influence LC dynamics and NE metabolism. We hypothesize NE metabolism/trafficking as a target for dieldrin, producing elevated levels of DOPEGAL which affects Tau processing and yields Tau aggregation. In addition, we posit that modulation of ECM as the second “hit” that influences cellular responses to dieldrin. The proposed work is highly relevant to AD neuropathogenesis and builds upon the previously funded application. The goal of this supplement is to elucidate mechanisms underlying environmental risk factors for AD, specifically focusing on the interaction of the pesticide dieldrin with NE metabolism in neurons and the role of the ECM. The central hypothesis is that dieldrin targets NE metabolism and/or trafficking in neurons, yielding build-up of reactive metabolites that initiate toxic pathways, such as tau fibrillization, injuring neurons in an ECM-dependent manner. Two specific aims will be completed: 1) Elucidate the outcomes of pesticide/dieldrin exposure on noradrenergic cells for production of the toxic species DOPEGAL. 2) Determine the contribution of the ECM to pesticide- and DOPEGAL-mediated cellular injury. These Specific Aims will build upon previous work to address key mechanistic questions for AD regarding critical cellular interactions yielding vulnerability of neurons to pesticides. These innovative studies are significant to identifying key mechanistic targets of neurotoxic pesticides and to identifying potential biomarkers for individuals at risk for developing AD.

项目摘要。接触有机氯狄氏剂会使人容易患帕金森病。疾病 (PD)；然而，接触狄氏剂会破坏 DA 的机制尚不清楚。但仅靠稳态可能不足以减少多巴胺（DA）神经元的损失，并且神经退行性变可能一些动物模型已经证明，改变 DA 稳态，新陈代谢和/或运输，导致 DA 神经元逐渐丧失；因此，遗传变异修饰； DA 代谢可能是一个额外的“打击”，与农药接触的破坏具有毒性协同作用。体内平衡会产生有毒中间体，例如 ROS 和醛（3,4-二羟基苯乙醛， DOPAL），通过单胺氧化酶，与 PD 类似，有证据表明狄氏剂是阿尔茨海默病的危险因素。疾病 (AD) 有人提出，NE 稳态的改变与有毒物质的产生有关。与 AD 相关的细胞损伤与 DA 一样，NE 通过单胺氧化酶生物转化为醛 (3,4-)。二羟基苯乙醇醛（DOPEGAL），具有高蛋白质反应性和毒性。神经病理学发生在蓝斑 (LC)，这是大脑中 NE 神经支配的主要部位，涉及 Tau 蛋白被天冬酰胺蛋白酶 (AEP) 裂解后的神经原纤维缠结。报告表明，NE 代谢物 DOPEGAL 可激活 AEP 裂解 Tau 并诱导 Tau 细胞外基质 (ECM) 的调节被认为对于 AD 病理学很重要，并且可能。影响 LC 动力学和 NE 代谢，我们帮助 NE 代谢/贩运作为狄氏剂的目标，产生高水平的 DOPEGAL，影响 Tau 加工并产生 Tau 聚集。我们认为 ECM 的调节是影响细胞对狄氏剂反应的第二个“打击”。拟议的工作与 AD 神经发病机制高度相关，并建立在先前资助的申请的基础上。本补充品的目的是阐明 AD 环境风险因素的潜在机制，特别关注农药狄氏剂与神经元 NE 代谢的相互作用以及 ECM 的中心假设是狄氏剂以 NE 代谢和/或神经元运输为目标，产生反应性代谢物的积累会启动毒性途径，例如 tau 纤维化，从而损伤神经元依赖 ECM 的方式将完成两个具体目标：1）阐明农药/狄氏剂的结果。暴露于去甲肾上腺素能细胞以产生有毒物质 DOPEGAL 2) 确定 DOPEGAL 的贡献。针对农药和 DOPEGAL 介导的细胞损伤的 ECM 这些具体目标将建立在先前的基础上。致力于解决 AD 的关键机制问题，涉及关键的细胞相互作用，从而产生脆弱性这些创新研究对于确定农药的关键机制目标具有重要意义。神经毒性农药，并确定有患 AD 风险的个体的潜在生物标志物。