Gut Neuroendocrine Cell Signaling

帕金森病(PD)是一种进行性神经退行性疾病，导致剧烈运动 疾病以及胃瘫和便秘等胃肠道症状。帕金森病的原因不明 而且这种疾病也没有治愈的办法。帕金森病在退伍军人管理局很常见，超过4万名退伍军人在退伍军人管理局接受治疗 每年都有医疗设施。有证据表明，环境毒素，如杀虫剂，鱼藤酮和 这种名为橙剂的除草剂可能是导致帕金森氏症的原因之一。退伍军人暴露在 橙剂会增加帕金森病的发病率，医学研究所在其报告中得出结论 “退伍军人和橙剂：更新2008年”，“暴露在橙剂和其他除草剂中 越战与患帕金森氏症的几率增加有关。 认识到帕金森病与服兵役期间接触橙剂有关。尽管 环境毒素暴露与帕金森病之间的关系，环境毒素如何引起帕金森病尚不清楚。 帕金森病的病理特征是大脑和大脑中的胞浆内含物，称为路易小体 肠道神经系统。这些包涵体与脑内多巴胺能神经元的变性有关。 黑质致密部，产生明显的运动和迷走神经障碍 功能障碍。路易氏病理的主要成分是聚集的α-突触核蛋白，它是一种与 错折和聚集的倾向。错折叠α-突触核蛋白在帕金森病发病机制中的重要作用 证据支持一种模型，在该模型中，路易氏病变的传播是通过细胞间传播的 错误地将α-突触核蛋白折叠到受体细胞上。错误折叠的α-突触核蛋白在受体体内招募天然α-突触核蛋白 细胞，并充当最终导致形成的聚集体的模板或核心 路易身体和最终的警局。有证据表明，帕金森病先从肠道开始，然后影响大脑。为 例如，在帕金森病患者的大脑中以异常形式发现的α-突触核蛋白出现在 在它出现在大脑之前，在肠道神经中形成。此外，切断迷走神经(迷走神经切断术)可以减少 发展为帕金森病的风险。然而，了解环境毒素是如何导致α异常形式的- 缺乏在肠道神经系统中形成的突触核蛋白。 肠内分泌细胞(EECS)是肠道内层的一种特殊的感觉细胞。在这个地点， EECS暴露在食物和摄入的环境毒素中。我们最近有了两个重要的发现。 首先，我们发现EECs与神经相连，从而提供了一条从肠道到大脑的直接路径。 第二，我们发现EECs表达α-突触核蛋白，可能是异常α-突触核蛋白的来源。 可能会扩散到大脑。为了调查这种可能性，我们将进行概念验证研究，以 使用体外培养的肠上皮细胞模型、含有肠上皮细胞的肠道器官、以及 在小鼠模型中，动物暴露在环境毒素鱼藤酮和橙剂中。我们 已经开发了工具来定位和表征肠道和肠内皮细胞中不同形式的α-突触核蛋白 太紧张了。我们将确定潜在的神经毒素是否会影响α-突触核蛋白的基因表达、蛋白质丰度和 在EEC细胞系和培养中的肠道器官中聚集。然后我们将进行详细的喂养 研究确定鱼藤酮和橙剂是否会导致大脑皮层细胞中α-突触核蛋白的类似变化。 因此，这些研究将检验环境毒素导致α-突触核蛋白异常的假设 在EECS中形成，然后扩散到神经系统，导致帕金森病。这一新知识将形成 为进一步研究帕金森病患者外周血管内皮细胞中α-突触核蛋白的特性奠定基础。最终，这些研究可能 导致了帕金森氏症最早阶段的诊断测试的开发 目前可以诊断疾病。此外，如果我们的理论得到支持，这可能会导致新的方法 帕金森氏症的预防或治疗。

Parkinson’s disease (PD) is a progressive neurodegenerative disease that results in severe movement disorders and gastrointestinal symptoms such as gastroparesis and constipation. The cause of PD is unknown and there is no cure for the disease. PD is common in the VA and over 40,000 veterans are treated in VA medical facilities each year. There is evidence that environmental toxins such as the pesticide, rotenone, and the herbicide, Agent Orange, may play a role in causing Parkinson’s disease. Military veterans exposed to Agent Orange have an increased incidence of PD and the Institute of Medicine concluded in its report “Veterans and Agent Orange: Update 2008”, that "exposure to Agent Orange and other herbicides used during the Vietnam War is associated with an increased chance of developing Parkinson's disease." As a result, VA recognized that PD was associated with exposure to Agent Orange during military service. Despite the association between environmental toxin exposure and PD, how environmental toxins cause PD is unknown. The pathological hallmarks of PD are cytoplasmic inclusions known as Lewy bodies in the brain and enteric nervous system. These inclusions are associated with degeneration of dopaminergic neurons in the substantia nigra pars compacta which produces the distinctive disorders of movement and vagal nerve dysfunction. The major component of Lewy pathology is aggregated α-synuclein, a synaptic protein with the propensity to misfold and aggregate. Misfolded α-synuclein plays a critical role in PD pathogenesis and recent evidence supports a model in which propagation of Lewy pathology occurs via cell-to-cell transmission of misfolded α-synuclein onto recipient cells. Misfolded α-synuclein recruits native α-synuclein in the recipient cell and acts as a template or nidus for the development of aggregates that eventually lead to formation of Lewy bodies and ultimately PD. There is evidence that PD starts in the gut before affecting the brain. For example, α-synuclein, which is found in an abnormal form in the brains of PD patients, appears in abnormal form in gut nerves before it appears in the brain. Moreover, cutting the vagus nerve (vagotomy) reduces the risk of developing PD. Nevertheless, understanding how environmental toxins cause the abnormal form of α- synuclein to form in the nervous system of the gut is lacking. Enteroendocrine cells (EECs) are specialized sensory cells in the lining of the gut. In this location, EECs are exposed to food and ingested environmental toxins. We recently made two important discoveries. First, we discovered that EECs connect to nerves, thus providing a direct route from the intestine to the brain. Second, we discovered that EECs express α-synuclein and may be the source of abnormal α-synuclein that could spread to the brain. To investigate this possibility, we will perform proof-of-concept studies to characterize α-synuclein in EECs using a model of EECs in vitro, intestinal organoids that contain EECs, and in mouse models in which animals are exposed to the environmental toxins rotenone and Agent Orange. We have developed tools to localize and characterize different forms of α-synuclein in EECs of the gut and in nerves. We will determine if potential neurotoxins affect α-synuclein gene expression, protein abundance, and aggregation in an EEC cell line and in intestinal organoids in culture. We will then perform detailed feeding studies to determine if rotenone and Agent Orange cause similar changes to α-synuclein in their EECs. Therefore, these studies will test the hypothesis that environmental toxins induce abnormal α-synuclein formation in EECs that then spread to the nervous system to cause PD. This new knowledge will form the basis for future studies to characterize α-synuclein in EECs of patients with PD. Ultimately these studies could lead to the development of a diagnostic test for the very earliest stages of Parkinson’s disease well before the disease can be diagnosed currently. In addition, if our theories are supported, this could lead to new methods of prevention or treatment for Parkinson’s disease.