The role of gut endocrine cells in Parkinson's Disease

描述(申请人提供)：肠内分泌细胞(EECS)是胃肠道的感觉细胞。其顶端表面向肠腔开放，其基底外侧表面含有丰富的分泌小泡，刺激细胞时会释放这些小泡。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，肠道的EECs具有许多神经元样特征，包括被称为神经荚的轴突样突起。正是通过神经荚，EECs与神经元相连。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的方式。胃肠道通过有时含有除草剂和杀虫剂的食物不断地暴露在环境中，肠道粘膜中的EECS是除草剂暴露的准备目标。流行病学和实验数据表明，环境中暴露于除草剂和杀虫剂是帕金森氏症的主要原因。帕金森病的特点是神经元内的路易小体由α-突触核蛋白聚集组成，突触核蛋白是一种可能保护神经免受毒性损伤的蛋白质。α-突触核蛋白的聚集体可以从一个细胞传递到另一个细胞，诱导聚集物形成一个类似于Pron的级联反应，在神经系统中传播。异常的α-突触核蛋白在扩散到大脑之前出现在肠道神经元中。因此，帕金森氏症发生在神经组织与环境密切相关的区域，如肠道，尽管这是如何发生的尚不清楚。在其神经元样特征中，我们发现EEC也表达α-突触核蛋白。这一发现提出了EECS是帕金森氏症的来源的可能性。我们认为，杀虫剂和除草剂导致大脑皮层细胞中异常的α-突触核蛋白，它被传递到肠道中的神经元，并扩散到神经系统。我们将通过确定已知的导致帕金森氏病的除草剂和杀虫剂是否在大脑皮层细胞中产生异常的α-突触核蛋白，以及大脑皮层细胞是否将α-突触核蛋白折叠到神经元来验证这一假设。这些研究将确定大脑皮层细胞是否是异常α-突触核蛋白的来源，这可能是帕金森病的根源。确定帕金森氏症的源头可能为未来的治疗提供新的靶点。

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 α-synuclein, a neuronal protein that may protect against toxic injury. Aggregates of α-synuclein can be passed from cell to cell, inducing aggregates in a "prion-like cascade" that spreads through the nervous system. Abnormal α-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 α-synuclein. This finding raises the possibility that EECs are the source of Parkinson's disease. We propose that pesticides and herbicides cause abnormal α-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 α-synuclein in EECs and if EECs transmit is folded α-synuclein to neurons. These studies will determine if EECs are the source of abnormal α-synuclein that could be the origin of Parkinson's disease. Identifying the source of Parkinson's disease may offer new targets for future therapy.