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氏病（PD）的发生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（PQ）和MANEB（MB）增加了PD的风险，但潜在的机制尚不清楚。线粒体氧化应激似乎是PD环境原因的核心，这是对抗氧化剂谷胱甘肽（GSH）的研究支持的。然而，最近的数据表明，过氧蛋白3（PRX3）是抗氧化剂硫氧还蛋白-2（TRX2）支持的过氧化物酶，在线粒体过氧化物代谢中具有主要作用。 TRX2的氧化通过线粒体通透性过渡和调节激酶1的凋亡信号的激活激活细胞死亡机制（Ask1）。拟议的研究旨在研究以下假设：TRX2/PRX3系统是Nigra中重要的线粒体抗氧化剂系统，该系统受到MB-启用PQ毒性破坏的替代性。为此，将使用两个由体外和体内模型组成的特定目标。在AIM 1中，多巴胺能SH-SY5Y细胞将用PQ，MB或组合处理，以评估应力反应，TRX2/PRX3氧化的增强以及细胞死亡途径的激活。这项研究将涉及线粒体和基于质谱的蛋白质组学分析的特定机理靶标。为了检查MB介导的作用，将测量醛脱氢酶活性和细胞内铜的积累。在AIM 2中，遗传小鼠模型（PRX3过度表达的小鼠）将用于研究PQ + MB体内PQ + MB的特定线粒体氧化还原作用。丰度和隔室氧化还原作用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衡量。这项研究将为将来将结果转化为人类研究的基础，在该研究中，可以提供裸露的农场工人的档案样本。最后，这些研究将提高对TRX2/PRX3系统在农药介导的神经变性中的机械作用的理解。 公共卫生相关性：据信农药暴露会导致帕金森氏病的发展，这影响了全球人口的1％。我们认为，这种影响是由于农药的结合而产生的，这些农药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。该项目旨在检验这一假设。