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.

抽象的 许多环境和遗传因素是帕金森氏神经元变性的基础 疾病（PD）。暴露于农药，例如烤面包酮和有机氯除草剂，例如2,4-D，主要是 越南战争中使用的橙色代理商的组成部分与PD的较高事件有关。 nigral da 神经元具有巨大的轴突树木化，并且特别容易受到微管 - 分解剂的影响。 先前的研究表明，许多环境PD毒素对微管的影响。我们以前的研究 体外和大鼠神经元培养物表明帕金与微管结合并稳定。在我们的 使用来自正常受试者的IPSC衍生的中脑DA神经元和PD患者的初步研究 突变，我们发现帕金突变显着降低了神经元的总长度和复杂性 通过破坏微管的稳定过程。此外，环境PD毒素（例如2,4-D）有很多 与正常的PD患者对PD患者的中脑DA神经元的毒性更高 控件。为了证明这些表型确实是由帕金引起的，我们将产生等源IPSC 通过修复PD患者IPSC中的Parkin突变，并通过对控制中引起PD PACKIN突变 ipscs。这些等生IPSC的线将用于检查PD环境毒素对人的影响 体外和大鼠大脑中的中脑DA神经元。该提案旨在研究帕金和环境PD 毒素对普通分子靶标（微管）的影响，以影响中脑多巴胺能的存活率 源自IPSC的同源性对神经元。单个人类ni骨神经元的独特形态， 估计其4.6米长的轴突树木，使该细胞特别容易受到遗传的影响（例如 帕克蛋白突变）或环境因素（例如鱼藤酮，2,4-d），使微管稳定。机理 从研究中获得的有关帕金受保护作用的洞察力将有助于识别 PD疾病改良疗法。