Molecular mechanisms contributing to intestinal α-synuclein aggregation and pathology in Parkinson´s Disease

帕金森病（PD）与α-突触核蛋白（α-Syn）聚集相关，导致中枢神经系统（CNS）神经元变性，引起运动表现。此外，PD患者常伴有胃肠功能障碍，胃肠功能障碍在运动症状出现前几年就已出现，目前被认为是该病的早期征兆。虽然疾病机制尚不清楚，但在PD患者的肠神经系统（ENS）中检测到病理性α-Syn。事实上，对肠脑轴的研究表明，α-Syn聚集可能发生在肠道，并传播到中枢神经系统，促进神经退行性变，但其机制尚不清楚。因此，在跨学科和翻译的方法中，我们旨在确定触发肠道α-Syn聚集的细胞来源和介质，及其对上皮稳态和粘膜炎症的影响。由于肠上皮内的肠内分泌细胞（Enteroendocrine Cells, EECs）表达α-Syn，我们将重点关注该细胞群在肠道α-Syn聚集中的作用，反之亦然，α-Syn对这些分泌性上皮细胞功能的影响。此外，我们将寻求描述α- syn负载的细胞外囊泡（EVs）作为肠-脑双向通信的途径。肠道α-Syn病理背后的机制可能解释前驱PD，并为生物标志物的鉴定和诊断/治疗策略的制定铺平道路。该项目的长期目标是确定肠道上皮功能障碍的特征，这些特征可以作为PD等神经退行性疾病的（早期）生物标志物。

Parkinson´s Disease (PD) is associated with α-synuclein (α-Syn) aggregation leading to neuronal degeneration in the Central Nervous System (CNS) causing motor manifestations. Besides this, PD patients often suffer from gastrointestinal dysfunction, which appears years before the occurrence of motor symptoms and is nowadays considered as an early sign of the disease. Although disease mechanisms are not well understood, pathological α-Syn has been detected in the Enteric Nervous System (ENS) of PD patients. Actually, studies on the gut-brain axis suggest that α-Syn aggregation may occur in the intestine and propagate to the CNS to promote neurodegeneration, but the mechanisms behind are elusive. Thus, in an interdisciplinary and translational approach, we aim at identifying cellular sources and mediators triggering intestinal α-Syn aggregation, and its impact on epithelial homeostasis and mucosal inflammation. Since Enteroendocrine Cells (EECs) within the intestinal epithelium express α-Syn, we will focus on the role of this cell population in the context of gut α-Syn aggregation, and vice versa, the impact of α-Syn on the function of these secretory epithelial cells. Moreover, we will seek at the description of α-Syn-loaded extracellular vesicles (EVs) as a route for bidirectional gut-brain communication. Mechanisms behind α-Syn pathology in the gut might explain prodromal PD and pave the way for the identification of biomarkers and the development of diagnosis/therapeutic strategies. The long-term vision of this project is to identify hallmarks of gut epithelial dysfunction which could serve as (early) biomarkers for neurodegenerative disorders, like PD.