The Interaction of parkin and environmental toxins in Parkinson’s disease

帕金森病中帕金蛋白与环境毒素的相互作用

• 批准号: 9898312
• 负责人: JIAN FENG
• 金额: --
• 依托单位: VA WESTERN NEW YORK HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898312
• 关键词: 2,4-Dichlorophenoxyacetic Acid; Address; Affect; Axon; Binding; Brain; Cells; Chlorinated Hydrocarbons; Complex; Disease; Dopamine; Electrophysiology (science); Environmental Impact; Environmental Risk Factor; Exhibits; Exposure to; Financial compensation; Genes; Genetic; Herbicides; Human; In Vitro; Incidence; Inherited; Knock-out; Length; Link; Methods; Microtubule Depolymerization; Microtubule Stabilization; Microtubules; Midbrain structure; Military Personnel; Mitochondria; Molecular Target; Morphology; Movement Disorders; Mus; Mutate; Mutation; Neurons; Parkinson Disease; Patients; Pesticides; Phenotype; Process; Property; Proteins; Rattus; Rotenone; Services; Technology; Testing; Toxic Environmental Substances; Toxic effect; Toxin; Transplantation; Ubiquitin; Vesicle; Veterans; Vietnam; War; agent orange; base; disability; disease phenotype; dopaminergic neuron; experimental study; genome editing; improved; in vivo; induced pluripotent stem cell; insight; meter; neuronal cell body; oxidation; parkin gene/protein; protective effect; repaired; stem

Abstract Many environmental and genetic factors underlie the degeneration of nigral DA neurons in Parkinson's disease (PD). Exposure to pesticides such as rotenone and organochlorine herbicides such as 2,4-D, a major component of Agent Orange used in Vietnam War, has been linked to higher incidence of PD. Nigral DA neurons have massive axon arborization and are particularly vulnerable to microtubule-depolymerizing agents. Previous studies show that many environmental PD toxins impact on microtubules. Our previous studies in vitro and in rat neuronal cultures have shown that parkin binds to and stabilizes microtubules. In our preliminary studies using iPSC-derived midbrain DA neurons from normal subjects and PD patients with parkin mutations, we found that parkin mutations markedly reduced the total length and complexity of neuronal processes by destabilizing microtubules. Furthermore, environmental PD toxins, such as 2,4-D, had much higher toxicity on midbrain DA neurons from PD patients with parkin mutations than those from normal controls. To demonstrate that these phenotypes are indeed caused by parkin, we will generate isogenic iPSC by repairing parkin mutations in PD patient iPSCs and by introducing PD-causing parkin mutations in control iPSCs. These lines of isogenic iPSCs will be used to examine the impact of PD environmental toxins on human midbrain DA neurons in vitro and in rat brains. The proposal aims to study how parkin and environmental PD toxins impact on a common molecular target – microtubules – to affect the survival of midbrain dopaminergic neurons derived from isogenic pairs of iPSCs. The unique morphology of a single human nigral DA neuron, with its estimated 4.6 meter long axon arborization, renders the cell particularly vulnerable to genetic (e.g. parkin mutations) or environmental factors (e.g. rotenone, 2,4-D) that destabilize microtubules. Mechanistic insights gained from the study on the protective effects of parkin would be useful for the identification of disease-modifying therapies for PD.

摘要 许多环境和遗传因素是帕金森病黑质DA能神经元变性的基础 疾病（PD）。接触鱼藤酮等农药和2，4-D等有机氯除草剂， 在越南战争中使用的橙子剂的成分，与帕金森病的发病率较高有关。黑质DA 神经元具有大量的轴突分支，并且特别易受微管解聚剂的影响。 以往的研究表明，许多环境PD毒素影响微管。我们以前的研究 在体外和大鼠神经元培养物中已经表明帕金蛋白结合到微管上并使其稳定。在我们 使用来自正常受试者和帕金森病患者的iPSC衍生的中脑DA神经元的初步研究 突变后，我们发现帕金突变显着减少了神经元的总长度和复杂性 通过破坏微管的稳定来进行。此外，环境PD毒素，如2，4-D， PD患者Parkin突变对中脑DA能神经元的毒性高于正常人 对照为了证明这些表型确实是由parkin引起的，我们将产生同基因iPSC， 通过修复PD患者iPSC中的帕金突变和通过在对照组中引入引起PD的帕金突变， iPSCs。这些同基因iPSC系将用于检查PD环境毒素对人类的影响。 中脑DA能神经元的体外培养和大鼠脑内的培养。该提案旨在研究停车场和环境PD 毒素影响一个共同的分子靶点-微管-以影响中脑多巴胺能神经元的存活 来源于iPSC的同基因对的神经元。单个人类黑质DA神经元的独特形态， 由于其估计4.6米长的轴突树枝状结构，使得细胞特别容易受到遗传（例如， parkin突变）或环境因素（如鱼藤酮，2，4-D），使微管不稳定。机械论 从帕金的保护作用的研究中获得的见解将有助于确定 PD的疾病改善疗法。