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Pesticide-mediated inhibition of UBA1 and cumulative risk for Parkinson's Disease

农药介导的 UBA1 抑制和帕金森病的累积风险

基本信息

批准号：
8188050
负责人：
WILLIAM M VALENTINE
金额：
$ 35.1万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-11 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8188050
关键词：
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Affect Animal Model Benomyl Biochemical Biological Process Blood Brain Brain region Cell Signaling Process Cells Complex Corpus striatum structure Cyclin-Dependent Kinase 5 Data Developing Countries Development Disease Disease Progression Dose Drug Formulations Enteral Environmental Pollution Enzyme Inhibition Enzymes Etiology Event Ganglia General Population Genes Genetic Predisposition to Disease Goals Herbicides Illicit Drugs Immunohistochemistry In Vitro Incidence Individual Industrial fungicide Injury Intervention Investigation Lesion Maps Mediating Methods Modification Molecular Molecular Target Motor Mutation Nerve Degeneration Neurodegenerative Disorders Parents Parkinson Disease Parkinsonian Disorders Pathway interactions Patients Penetrance Pesticides Phosphorylation Population Predisposition Prevalence Process Processed Genes Proteins Rattus Regulation Risk Risk Management Role Screening procedure Shotguns Silver Staining method Stains Structure-Activity Relationship System Testing Toxic effect Transgenic Animals Triazines UCHL1 gene Ubiquitin Ubiquitin-Activating Enzymes Variant Work adduct base cytotoxicity design dopamine transporter dopaminergic neuron environmental agent enzyme activity exposed human population gene environment interaction genome-wide in vivo inhibitor/antagonist liquid chromatography mass spectrometry loss of function mutation multicatalytic endopeptidase complex nigrostriatal pathway novel parkin gene/protein protein activation protein degradation protein function research study response synuclein tau Proteins tau phosphorylation

项目摘要

DESCRIPTION (provided by applicant): The prevalence of Parkinson's disease (PD) is increasing and predicted to double in the US and more than double in developing countries during the next 25 years; however a definite etiology or unifying sequence of molecular events for the most common form of PD, late onset sporadic idiopathic PD, has not been established. The long term goal of this project is to delineate mechanisms of environmental agents that contribute to increased risk for PD. The ubiquitin pathway has been implicated as a target for environmental agents based upon familial forms of PD resulting from loss of function mutations in Parkin and UCHL1 that are both components of the ubiquitin pathway. The experiments presented in this application are guided by the following working Hypothesis: The triazine and thiocarbamate herbicides, and the diaklydithiocarbamate and benomyl based fungicides covalently modify and inhibit UBA1 activating enzyme resulting in impaired ubiquitin based protein processing and cell signaling that promote neurodegenerative changes contributing to PD. This hypothesis will be tested through the following Specific Aims: 1) To determine in vivo in rats if the proposed pesticides or selected metabolites inhibit UBA1 activating enzyme and produce nigrostriatal toxicity. To achieve this aim we will determine the dose-response for brain UBA1 enzyme inhibition, characterize UBA1 covalent modifications by shotgun LC/MS/MS, map neurodegenerative changes and quantify the expression and phosphorylation of tau and -synuclein. 2) To determine if in vitro inhibition of UBA1 contributes to dopaminergic neuron cytotoxicity, activation of Cdk5 and altered processing of gene products associated with sporadic PD. To achieve this aim MN9D cells will be used to modulate UBA1 expression and determine the influence of constitutively compromised and increased UBA1 function on viability, the expression and phosphorylation state of -synuclein and tau proteins, activation of Cdk5 and expression and localization of the dopamine transporter in cells exposed to the proposed pesticides, their metabolites or specific pharmacologic UBA1 inhibitors. The data derived from the proposed studies will assist in the formulation of more informed risk management and the development of screening methods to identify and predict other agents that act through similar or additive mechanisms. Identification of environmental agents that contribute to the development of PD either directly or through gene-environment interactions will facilitate strategies of intervention to decrease the risk of PD and slow the progression of disease in PD patients. PUBLIC HEALTH RELEVANCE: Parkinson's disease is the second most common neurodegenerative disease, currently has no cure and is increasing in incidence. This study will determine whether four major classes of pesticides can contribute to the development of Parkinson's disease through a common mechanism. These investigations will help to identify environmental agents that increase the risk for Parkinson's disease and will facilitate strategies to decrease this risk and slow the progression of Parkinson's disease.

描述（由申请人提供）：帕金森病（PD）的患病率正在增加，预计在未来25年内，美国的患病率将增加一倍，发展中国家的患病率将增加一倍以上;然而，尚未确定最常见的PD形式（迟发性散发性特发性PD）的明确病因或分子事件的统一序列。该项目的长期目标是描述导致PD风险增加的环境因子的机制。泛蛋白途径已被认为是环境因子的靶标，其基于由帕金和UCHL 1的功能缺失突变引起的家族性PD形式，帕金和UCHL 1均为泛蛋白途径的组分。本申请中提出的实验由以下工作假设指导：三嗪和硫代氨基甲酸酯除草剂以及基于二烷基二硫代氨基甲酸酯和苯菌灵的杀真菌剂共价修饰并抑制UBA 1活化酶，导致基于泛素的蛋白质加工和细胞信号传导受损，其促进促成PD的神经退行性变化。该假设将通过以下具体目的进行检验：1）在大鼠体内确定拟议的农药或选定的代谢物是否抑制UBA 1活化酶并产生黑质纹状体毒性。为了实现这一目标，我们将确定脑UBA 1酶抑制的剂量反应，通过鸟枪LC/MS/MS表征UBA 1共价修饰，映射神经退行性变化，并量化tau和-突触核蛋白的表达和磷酸化。2)确定UBA 1的体外抑制是否有助于多巴胺能神经元细胞毒性、Cdk 5激活和与散发性PD相关的基因产物加工改变。为了实现这一目标，MN 9D细胞将用于调节UBA 1表达，并确定组成性受损和增加的UBA 1功能对生存力的影响，-突触核蛋白和tau蛋白的表达和磷酸化状态，Cdk 5的激活和多巴胺转运蛋白在暴露于所提出的农药，其代谢物或特定的药理学UBA 1抑制剂的细胞中的表达和定位。从拟议的研究中获得的数据将有助于制定更知情的风险管理和筛选方法，以确定和预测通过类似或附加机制发挥作用的其他制剂。识别直接或通过基因-环境相互作用促进PD发展的环境因子，将有助于降低PD风险和减缓PD患者疾病进展的干预策略。公共卫生相关性：帕金森病是第二大常见的神经退行性疾病，目前尚无治愈方法，发病率正在上升。这项研究将确定四种主要类别的农药是否可以通过共同的机制促进帕金森病的发展。这些研究将有助于确定增加帕金森病风险的环境因素，并将促进降低这种风险和减缓帕金森病进展的策略。