The role of gut endocrine cells in Parkinson's Disease

肠道内分泌细胞在帕金森病中的作用

• 批准号: 9234533
• 负责人: Rodger A. Liddle
• 金额: $ 35.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234533
• 关键词: Apical; Axon; Brain; Brain Diseases; Cell Surface Receptors; Cells; Communication; Data; Digestion; Disease; Eating; Enteral; Enterocytes; Enteroendocrine Cell; Environment; Environmental Exposure; Epidemiology; Epithelial Cells; Exposure to; Food; Future; Gastrointestinal tract structure; Herbicides; Injury; Intestines; Lewy Bodies; Molecular; Mucous Membrane; Nervous system structure; Neurodegenerative Disorders; Neurons; Paraquat; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Pesticides; Process; Proteins; Rabies virus; Role; Rotenone; Secretory Vesicles; Sensory; Signal Transduction; Source; Surface; Synapses; Synaptic Vesicles; Testing; Tissues; Toxicant exposure; alpha synuclein; gastrointestinal epithelium; gut endocrine cell; insight; neurofilament; novel; pathogen; presynaptic neurons; prion-like; protein aggregate; public health relevance; relating to nervous system; synuclein; toxicant; vesicular release

 DESCRIPTION (provided by applicant): Enteroendocrine cells (EECs) are sensory cells of the gastrointestinal tract. Their apical surface is open to the lumen of the intestine and their basolateral surface contains abundant secretory vesicles that are released upon stimulation of the cell. Through specific cell surface receptors, EECs sense food as it passes through the intestine. We recently discovered that EECs of the gut possess many neuron-like features including axon-like processes known as neuropods. It is through neuropods that EECs connect to neurons. This neural connection provides a direct communication from the gut to the brain and is how the brain senses luminal contents. The gastrointestinal tract is constantly exposed to the environment through food that sometimes harbors herbicides and pesticides and EECs in the gut mucosa are ready targets for herbicide exposure. Epidemiological and experimental data indicate that environmental exposure to herbicides and pesticides is a major cause of Parkinson's disease. Parkinson's disease is characterized by intraneuronal Lewy bodies that consist of aggregates of -synuclein, a neuronal protein that may protect against toxic injury. Aggregates of -synuclein can be passed from cell to cell, inducing aggregates in a "prion-like cascade" that spreads through the nervous system. Abnormal -synuclein appears in enteric neurons before it spreads to the brain. Therefore, Parkinson's disease arises in regions where neural tissues are in close proximity to the environment, such as the gut, although how this occurs is unknown. Among their neuron-like features we discovered that EECs also express -synuclein. This finding raises the possibility that EECs are the source of Parkinson's disease. We propose that pesticides and herbicides cause abnormal -synuclein in EECs that is transmitted to neurons in the gut and spreads to the nervous system. We will test this hypothesis by determining if herbicides and pesticides known to cause Parkinson's disease produce abnormal -synuclein in EECs and if EECs transmit is folded -synuclein to neurons. These studies will determine if EECs are the source of abnormal -synuclein that could be the origin of Parkinson's disease. Identifying the source of Parkinson's disease may offer new targets for future therapy.

 描述（由申请方提供）：肠内分泌细胞（EEC）是胃肠道的感觉细胞。它们的顶面向肠腔开放，它们的基底面含有丰富的分泌囊泡，这些囊泡在细胞刺激时释放。通过特定的细胞表面受体，EECs在食物通过肠道时感知食物。我们最近发现，肠的EECs具有许多神经元样特征，包括被称为神经足的轴突样过程。EECs通过neuropods连接到神经元。这种神经连接提供了从肠道到大脑的直接通信，也是大脑感知管腔内容物的方式。胃肠道通过食物不断暴露于环境中，这些食物有时含有除草剂和杀虫剂，肠道粘膜中的EEC是除草剂暴露的现成目标。流行病学和实验数据表明，环境暴露于除草剂和杀虫剂是帕金森病的主要原因。帕金森病的特征在于神经元内路易体，其由β-突触核蛋白的聚集体组成，β-突触核蛋白是一种可以保护免受毒性损伤的神经元蛋白。β-突触核蛋白的聚集体可以从一个细胞传递到另一个细胞，以“朊病毒样级联”的方式诱导聚集体，并通过神经系统传播。异常的β-突触核蛋白在扩散到大脑之前出现在肠神经元中。因此，帕金森病发生在神经组织与环境（如肠道）密切相关的区域，尽管这种情况如何发生尚不清楚。在它们的神经元样特征中，我们发现EECs也表达β-突触核蛋白。这一发现提出了EECs是帕金森病来源的可能性。我们认为，杀虫剂和除草剂导致异常的β-突触核蛋白在EECs，这是在肠道神经元和传播到神经系统。我们将通过确定已知引起帕金森氏病的除草剂和杀虫剂是否在EEC中产生异常的β-突触核蛋白以及EEC是否将折叠的β-突触核蛋白传递给神经元来验证这一假设。这些研究将确定EEC是否是异常β-突触核蛋白的来源，而异常β-突触核蛋白可能是帕金森病的起源。确定帕金森病的来源可能为未来的治疗提供新的靶点。