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。除此之外，PD患者经常患有胃肠道功能障碍，其在运动症状发生前数年出现，并且现在被认为是疾病的早期体征。虽然疾病机制尚未完全了解，但在PD患者的肠神经系统（ENS）中已检测到病理性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CNS以促进神经退行性变，但其背后的机制尚不清楚。因此，在一个跨学科和翻译的方法，我们的目标是确定细胞来源和介质触发肠道α-Syn聚集，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（EECs）表达α-Syn，因此我们将重点关注该细胞群在肠道α-Syn聚集背景下的作用，反之亦然，α-Syn对这些分泌上皮细胞功能的影响。此外，我们将寻求描述α-Syn-loaded细胞外囊泡（EV）作为双向肠-脑通讯的途径。肠道中α-Syn病理学背后的机制可能解释前驱PD，并为识别生物标志物和开发诊断/治疗策略铺平道路。该项目的长期愿景是确定肠道上皮功能障碍的标志，这些标志可以作为神经退行性疾病（如PD）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.