Gut Neuroendocrine Cell Signaling

帕金森病（PD）是一种进行性神经退行性疾病，导致严重的运动障碍， 疾病和胃肠道症状，如胃轻瘫和便秘。PD的原因不明 而且这种病无法治愈PD在VA中很常见，超过40，000名退伍军人在VA接受治疗 每年的医疗设施。有证据表明，环境毒素，如农药，鱼藤酮， 除草剂橙子可能是导致帕金森病的原因之一。退伍军人暴露于 药剂橙子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， “退伍军人和橙子剂：2008年更新”，“暴露于橙子剂和其他除草剂使用期间， 越南战争与帕金森病发病率的增加有关。“因此，VA 认识到帕金森病与服兵役期间接触橙子剂有关。尽管 环境毒素暴露与PD之间的关联，环境毒素如何导致PD尚不清楚。 PD的病理学标志是脑中被称为路易体的细胞质内含物， 肠神经系统。这些包涵体与多巴胺能神经元的变性有关， 产生运动和迷走神经的独特障碍的黑质 功能障碍Lewy病理学的主要成分是聚集的α-突触核蛋白，一种突触蛋白， 错误折叠和聚集的倾向。错误折叠的α-突触核蛋白在PD发病机制中起关键作用， 有证据支持一种模型，其中路易病的传播是通过细胞间的传递发生的， 错误折叠的α-突触核蛋白转移到受体细胞上。错误折叠的α-突触核蛋白在受体中募集天然α-突触核蛋白 细胞，并作为模板或聚集体的发展，最终导致形成 路易体最终导致帕金森病有证据表明，PD在影响大脑之前始于肠道。为 例如，在PD患者的大脑中以异常形式发现的α-突触核蛋白， 在出现在大脑之前就在肠道神经中形成。此外，切断迷走神经（迷走神经切断术）减少了 发展PD的风险。然而，了解环境毒素如何导致α- 在肠道神经系统中形成突触核蛋白的能力缺乏。 肠内分泌细胞（EECs）是肠道内层的特化感觉细胞。在这个地方， EEC暴露于食物和摄入的环境毒素。我们最近有两个重大发现。 首先，我们发现EECs连接到神经，从而提供了从肠道到大脑的直接途径。 其次，我们发现内皮细胞表达α-突触核蛋白，并且可能是异常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， 使用体外EEC模型表征EEC中的α-突触核蛋白，含有EEC的肠类器官，以及 在小鼠模型中，动物暴露于环境毒素鱼藤酮和橙子剂。我们 已经开发了工具来定位和表征肠道和肠外的EECs中不同形式的α-突触核蛋白， 神经我们将确定潜在的神经毒素是否影响α-突触核蛋白基因表达，蛋白质丰度， 在EEC细胞系和培养物中的肠类器官中的聚集。然后我们将执行详细的喂养 研究，以确定鱼藤酮和代理橙子引起类似的变化，α-突触核蛋白在他们的内皮细胞。 因此，这些研究将检验环境毒素诱导异常α-突触核蛋白的假设 在EECs中形成，然后扩散到神经系统，导致PD。这些新知识将构成 为进一步研究PD患者EEC中α-突触核蛋白的特征奠定了基础。最终，这些研究可以 导致帕金森病最早阶段的诊断测试的发展， 目前可以确诊的疾病。此外，如果我们的理论得到支持，这可能会导致新的方法 预防或治疗帕金森病的方法。

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.