Mitochondrial Oxidative Stress and Protection in Pesticide-induced Neurotoxicity

农药引起的神经毒性中的线粒体氧化应激和保护

• 批准号: 7516477
• 负责人: JIYANG CAI
• 金额: $ 18.8万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7516477
• 关键词: 1-Methyl-4-phenylpyridinium; Affect; Animal Model; Apoptosis; Autopsy; Brain; Carbamates; Case Study; Caspase; Cell Proliferation; Cells; Chaperonin 60; Chronic; Clinical; Condition; Cytoplasm; Down-Regulation; Embryo; Ensure; Environmental Risk Factor; Epidemiologic Studies; Etiology; Event; Exposure to; Family; Functional disorder; Gene Mutation; Genetic; Glutathione; Human; Incidence; Individual; Injury; Ions; Lead; Lewy Bodies; Link; Maneb; Manganese Superoxide Dismutase; Measures; Mediator of activation protein; Mitochondria; Mitochondrial Proteins; Molecular; Molecular Target; Mutation; NADH dehydrogenase (ubiquinone); Neuroblastoma; Neurons; Nuclear; Numbers; Oxidants; Oxidation-Reduction; Oxidative Stress; Paraquat; Parkinson Disease; Parkinsonian Disorders; Pathology; Patients; Permeability; Peroxides; Pesticides; Play; Process; Protein Import; Protein Overexpression; Protein Precursors; Proteins; Rattus; Reporting; Research Personnel; Risk; Role; Rotenone; Rural; Signal Transduction; Small Interfering RNA; Stress; Substantia nigra structure; System; Testing; Thioredoxin; Toxic Environmental Substances; Toxic effect; Ubiquitin; base; cytochrome c; dopaminergic neuron; epidemiology study; farmer; gene environment interaction; inhibitor/antagonist; mitochondrial dysfunction; multicatalytic endopeptidase complex; novel; oxidation; pars compacta; pesticide exposure; pesticide induced neurotoxicity; programs; protective effect; protein degradation; residence; response; synuclein; thioredoxin reductase; toxicant

The etiology of Parkinson's disease (PD) involves gene/environment interaction. While most of the identified genetic mutations affect the ubiquitin-proteasome system (UPS), epidemiological studies and clinical case reports have strongly suggested the association between pesticide exposure and increased incidence of PD. In animal models, selective toxicities to the nigrostriatal dopaminergic neurons occur after systemic exposure to rotenone and paraquat. Oxidative stress is a common mediator of pesticide-induced neurotoxicity. It contributes to PD-related pathological changes such as formation of a-synuclein aggregates and inhibition of proteasomal function. However, the molecular targets of oxidative damage have not been clearly defined and the mechanistic link between mitochondria! and proteasomal dysfunction remains to be determined. In our preliminary studies, we have shown that mitochondrial thioredoxin (mtTrx; Trx2) is particularly susceptible to oxidation induced by a variety of environmental toxicants, including peroxides, rotenone, MPP+ and paraquat. Submicromolar concentrations of rotenone induced persistent oxidation of mtTrx and redistribution of mtTrx to the cytoplasm. Chronic exposure to nanomolar concentrations of rotenone resulted in decreased mtTrx protein. Overexpression of mtTrx protected cells from oxidant-induced apoptosis and inhibited a-synuclein aggregation caused by chronic rotenone toxicity. Downregulation of the mitochondrial thioredoxin reductase (TrxR 2) led to decreased mature mtTrx while increased its precursor form. Furthermore, we identified that mtTrx interacted with mitochondrial heat shock protein 60 which is a key component of the mitochondrial protein processing machinery. Based on these findings, we hypothesize that selective targeting of mtTrx by pesticides and the ensuring oxidation of mtTrx lead to impaired mitochondrial protein import. The hypothesis will be tested with two specific aims. Specific aim 1 is to determine whether the redox status and expression level of mtTrx control the sensitivity to pesticide-induced toxicity in cultured neuronal cells. Specific aim 2 is to determine whether the pesticide-induced oxidation inhibits the import of mtTrx and other nuclear DMA-encoded mitochondrial proteins. Results from these studies will define novel protein targets of oxidative injury and will facilitate our understanding towards the molecular mechanisms of environmental toxicities associated with PD.

帕金森病（Parkinson's disease，PD）的病因学涉及基因/环境相互作用。虽然大多数已确定的人 基因突变影响泛素-蛋白酶体系统（UPS），流行病学研究和临床病例 报告强烈建议农药暴露和PD发病率增加之间的关联。 在动物模型中，全身暴露后对黑质纹状体多巴胺能神经元产生选择性毒性 鱼藤酮和百草枯。氧化应激是农药神经毒性的一种常见介质。它 有助于PD相关的病理学变化，例如α-突触核蛋白聚集体的形成和抑制 蛋白酶体功能然而，氧化损伤的分子靶点尚未明确 和线粒体之间的机械联系！蛋白酶体功能障碍仍有待确定。在 我们的初步研究表明，线粒体硫氧还蛋白（mtTrx; Trx 2）特别是 易受各种环境毒物，包括过氧化物，鱼藤酮， MPP+和百草枯。亚微摩尔浓度的鱼藤酮诱导mtTrx的持续氧化， mtTrx向细胞质的再分布。长期暴露于纳摩尔浓度的鱼藤酮导致 减少mtTrx蛋白。过表达mtTrx可保护细胞免受氧化剂诱导的凋亡， 抑制由慢性鱼藤酮毒性引起的α-突触核蛋白聚集。线粒体下调 硫氧还蛋白还原酶（TrxR 2）导致成熟mtTrx减少而前体形式增加。 此外，我们发现mtTrx与线粒体热休克蛋白60相互作用，这是一个关键， 线粒体蛋白质加工机器的组成部分。基于这些发现，我们假设 农药对mtTrx的选择性靶向作用和确保mtTrx的氧化导致受损， 线粒体蛋白输入。将以两个具体目标来检验这一假设。具体目标1： 确定mtTrx的氧化还原状态和表达水平是否控制农药诱导的敏感性 在培养的神经细胞中的毒性。具体目标2是确定农药诱导的氧化是否 抑制mtTrx和其他核DMA编码的线粒体蛋白的输入。从这些 研究将确定新的蛋白质目标的氧化损伤，并将促进我们的理解， 与PD相关的环境毒性的分子机制。