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

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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.