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

• 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
• 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' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' 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

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.

项目总结。接触有机氯狄氏剂易患帕金森氏症 疾病(PD)；然而，暴露于疾病的机制尚不清楚。狄氏剂可扰乱DA 动态平衡本身可能不足以导致多巴胺(DA)神经元的丧失，而神经退行性变可能 需要一个额外的“命中”。几个动物模型已经证明，改变DA的动态平衡， 代谢和/或运输，导致DA神经元的进行性丧失；因此，遗传变异改变了 DA代谢可能是另一种与农药接触具有毒性协同作用的“打击”。DA中断 动态平衡产生有毒的中间体，如ROS和醛(3，4-二羟基苯乙醛， DOPAL)，通过单胺氧化酶。与帕金森病相似，有证据表明狄氏剂是阿尔茨海默氏症的危险因素 疾病(AD)。有人提出，NE动态平衡的改变与有毒物种的产生有关 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)，具有高度的蛋白质活性和毒性。公元早期 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 被天冬酰胺酶(AEP)切割后，Tau蛋白的神经纤维缠绕在一起。近期 研究表明，去甲肾上腺素的代谢物DOPEGAL能激活AEP裂解Tau并诱导Tau 聚合。细胞外基质(ECM)的调节被认为在AD病理中很重要，并可能 影响LC动力学和NE代谢。我们假设NE代谢/运输是狄氏剂的靶标， 产生高水平的DOPEGAL，这会影响Tau的加工并产生Tau聚集。此外, 我们假设细胞外基质的调节是影响细胞对狄氏剂反应的第二个“冲击”。这个 拟议的工作与阿尔茨海默病神经发病机制高度相关，并建立在先前资助的应用基础上。 本附录的目的是阐明阿尔茨海默病环境风险因素的潜在机制， 重点介绍了杀虫剂狄氏剂与去甲肾上腺素代谢在神经元中的相互作用及其作用。 ECM。中心假说是狄氏剂以去甲肾上腺素代谢和/或神经元运输为靶点，产生 活性代谢物的积聚，启动毒性途径，如tau纤维化，损伤神经元。 ECM依赖的方式。将完成两个具体目标：1)阐明农药/狄氏剂的结果 暴露在去甲肾上腺素能细胞上，以产生有毒物种DOPEGAL。2)确定以下项目的贡献 ECM对农药和DOPEGAL诱导的细胞损伤的影响。这些具体目标将建立在之前 致力于解决AD的关键机制问题，这些问题涉及关键的细胞交互作用，从而导致 从神经元到杀虫剂。这些创新性的研究对于确定关键的机制目标具有重要意义 神经毒性杀虫剂和为有患阿尔茨海默病风险的个人确定潜在的生物标志物。