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

基本信息

批准号：
7199443
负责人：
JIYANG CAI
金额：
$ 21.52万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7199443
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

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：帕金森病（PD）的病因涉及基因/环境相互作用。虽然大多数已发现的基因突变都会影响泛素蛋白酶体系统 (UPS)，但流行病学研究和临床病例报告强烈表明农药接触与 PD 发病率增加之间存在关联。在动物模型中，全身暴露于鱼藤酮和百草枯后，会对黑质纹状体多巴胺能神经元产生选择性毒性。氧化应激是农药引起的神经毒性的常见介质。它有助于 PD 相关的病理变化，例如 a-突触核蛋白聚集体的形成和蛋白酶体功能的抑制。然而，氧化损伤的分子靶点以及线粒体之间的机制联系尚未明确！蛋白酶体功能障碍仍有待确定。在我们的初步研究中，我们发现线粒体硫氧还蛋白（mtTrx；Trx2）特别容易受到各种环境毒物（包括过氧化物、鱼藤酮、MPP+ 和百草枯）诱导的氧化作用。亚微摩尔浓度的鱼藤酮诱导 mtTrx 持续氧化并将 mtTrx 重新分布到细胞质。长期暴露于纳摩尔浓度的鱼藤酮会导致 mtTrx 蛋白减少。 mtTrx 的过度表达可保护细胞免受氧化剂诱导的细胞凋亡，并抑制慢性鱼藤酮毒性引起的 α-突触核蛋白聚集。线粒体硫氧还蛋白还原酶 (TrxR 2) 的下调导致成熟 mtTrx 减少，同时其前体形式增加。此外，我们还发现 mtTrx 与线粒体热休克蛋白 60 相互作用，线粒体热休克蛋白 60 是线粒体蛋白质加工机制的关键组成部分。基于这些发现，我们假设农药选择性靶向 mtTrx 并确保 mtTrx 氧化会导致线粒体蛋白输入受损。该假设将通过两个具体目标进行检验。具体目标 1 是确定 mtTrx 的氧化还原状态和表达水平是否控制培养神经元细胞对农药诱导毒性的敏感性。具体目标 2 是确定农药诱导的氧化是否会抑制 mtTrx 和其他核 DMA 编码的线粒体蛋白的输入。这些研究的结果将确定氧化损伤的新蛋白质靶点，并将有助于我们理解与帕金森病相关的环境毒性的分子机制。