Mechanism of Peroxiredoxin 3 in a Model of Pesticide-Mediated Neurodegeneration

过氧化还原蛋白 3 在农药介导的神经变性模型中的作用机制

• 批准号: 8059443
• 负责人: James R Roede
• 金额: $ 5.11万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059443
• 关键词: 4 hydroxynonenal; Affect; Aldehydes; Alkylation; Americas; Antioxidants; Apoptosis; Apoptotic; Biological Assay; Brain; Catecholamines; Cell Death; Cells; Chemicals; Chemosensitization; Copper; Data; Development; Drug Metabolic Detoxication; Environmental Exposure; Epidemiology; Exposure to; Foundations; Future; Genetic; Glutathione; Herbicides; Human; Hydrogen Peroxide; In Vitro; Industrial fungicide; Injury; Investigation; Knowledge; Link; Lipid Peroxidation; MAP3K5 gene; Maneb; Manganese; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Metabolism; Methods; Midbrain structure; Mitochondria; Modeling; Movement Disorders; Mus; Nerve; Nerve Degeneration; Neurons; Organ; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; PRDX3 peroxidase; Paraquat; Parkinson Disease; Pathogenesis; Pathway interactions; Permeability; Peroxidases; Peroxides; Pesticides; Poison; Population; Proteins; Proteome; Proteomics; Research; Research Support; Risk; Role; Sampling; Substantia nigra structure; System; Testing; Thioredoxin-2; Tissues; Toxic effect; Transgenic Mice; Translating; Translations; Work; adduct; aldehyde dehydrogenases; base; biological adaptation to stress; design; dopaminergic neuron; environmental pesticide exposure; farm worker; in vivo; in vivo Model; innovation; metabolomics; mouse model; neurotoxicity; oxidation; oxidative damage; pesticide exposure; research study; response

DESCRIPTION (provided by applicant): Environmental pesticide exposure is connected to the occurrence of Parkinson's disease (PD), the most common neurodegenerative movement disorder in America. Epidemiological investigations indicate exposure to the pesticides paraquat (PQ) and maneb (MB) increase the risk of PD, but the underlying mechanisms are unknown. Mitochondrial oxidative stress appears to be central to environmental causes of PD, which is supported by research on the antioxidant glutathione (GSH). However, recent data show that peroxiredoxin 3 (Prx3), a peroxidase supported by the antioxidant thioredoxin-2 (Trx2), has a predominant role in mitochondrial peroxide metabolism. Oxidation of Trx2 activates cell death mechanisms through the mitochondrial permeability transition and activation of apoptosis signal regulating kinase-1 (ASK1). The proposed research is designed to investigate the hypothesis that the Trx2/Prx3 system is an important mitochondrial antioxidant system in the substatntia nigra that is disrupted by MB-potentiated PQ toxicity. To accomplish this, two specific aims consisting of in vitro and in vivo models will be used. In Aim 1, dopaminergic SH-SY5Y cells will be treated with PQ, MB or in combination to evaluate stress responses, potentiation of Trx2/Prx3 oxidation and activation of cell death pathways. This research will involve specific mechanistic targets of mitochondria and mass spectrometry-based proteomic analyses. To examine MB-mediated effects, aldehyde dehydrogenase activity and intracellular copper accumulation will be measured. In Aim 2, a genetic mouse model (Prx3 over- expressing mouse) will be used to study specific mitochondrial redox effects of PQ + MB in vivo. Abundance and compartmental redox effects will be measured by mass spectrometry-based proteomics and discovery- based metabolomic analyses. This research will provide a foundation for future translation of results into human studies, where archival samples from exposed farm workers are available. Lastly, these studies will advance the understanding of the mechanistic role of the Trx2/Prx3 system in pesticide-mediated neurodegeneration. PUBLIC HEALTH RELEVANCE: Pesticide exposure is believed to contribute to the development of Parkinson's disease, which affects 1% of the worldwide population. We believe that effects occur due to a combination of pesticides, which together disrupt key redox systems of mitochondria in affected nerve cells. This project is designed to test this hypothesis.

描述（由申请人提供）：环境农药暴露与帕金森病（PD）的发生有关，帕金森病是美国最常见的神经退行性运动障碍。流行病学调查表明，暴露于农药百草枯（PQ）和代森锰（MB）会增加PD的风险，但其潜在机制尚不清楚。线粒体氧化应激似乎是PD的环境原因的核心，这得到了抗氧化剂谷胱甘肽（GSH）研究的支持。然而，最近的数据表明，过氧化物氧还蛋白3（Prx 3），一种由抗氧化剂硫氧还蛋白2（Trx 2）支持的过氧化物酶，在线粒体过氧化物代谢中具有主导作用。Trx 2的氧化通过线粒体通透性转换和凋亡信号调节激酶-1（ASK 1）的激活来激活细胞死亡机制。拟议的研究旨在调查的假设，Trx 2/Prx 3系统是一个重要的线粒体抗氧化系统的substattntia黑，是由MB增强PQ毒性破坏。为了实现这一点，将使用两个特定的目标，包括体外和体内模型。在目的1中，将用PQ、MB或组合处理多巴胺能SH-SY 5 Y细胞，以评价应激反应、Trx 2/Prx 3氧化的增强和细胞死亡途径的激活。这项研究将涉及线粒体的特定机制目标和基于质谱的蛋白质组学分析。为了检查MB介导的作用，将测量醛脱氢酶活性和细胞内铜积累。在目的2中，将使用遗传小鼠模型（Prx 3过表达小鼠）研究PQ + MB的体内特异性线粒体氧化还原效应。将通过基于质谱的蛋白质组学和基于发现的代谢组学分析来测量绝对和房室氧化还原效应。这项研究将为将来将结果转化为人类研究提供基础，其中可以获得来自暴露农场工人的档案样本。最后，这些研究将推进对Trx 2/Prx 3系统在农药介导的神经变性中的机制作用的理解。 公共卫生相关性：农药暴露被认为有助于帕金森病的发展，影响全球1%的人口。我们认为，这些影响是由于杀虫剂的组合而发生的，它们共同破坏了受影响神经细胞中线粒体的关键氧化还原系统。本项目旨在验证这一假设。