Sebastiaan De Schepper

Parkinson’s disease (PD) is a progressive neurodegenerative disorder, characterized by alpha-synuclein (α-Syn) aggregation. Despite being the fastest-growing neurodegenerative condition in terms of patients affected, there are currently no disease-modifying treatments and diagnosis typically occurs after significant neurodegeneration has already taken place. Intervening in the prodromal phase remains the critical challenge, and gaining a deeper understanding of the underlying pathophysiology is essential. Compelling evidence suggests that α-Syn might aggregate early in the enteric nervous system, spreading to the brain via the vagus nerve and triggering immune cell

migration into the brain, where they contribute to disease progression. This project aims to address three key questions: 1) How are peripheral immune cells recruited to the brain in early α-Syn pathology? 2) How do peripheral immune cells interact with brain-resident cells to modulate the spread of α-Syn and neurodegeneration? 3) How do immune profile changes in the blood of high-risk prodromal PD patients relate to disease progression? To answer these questions, I will investigate the entry of peripheral immune cells to the brain using cutting-edge proximity and enzymatic labelling strategies; determine the immune interactome underlying α-Syn pathology and spread by combining α-Syn aggregation assays with in-situ spatial sequencing; and characterize circulating immune cells in prodromal PD patients by employing a humanized engraftment model to link peripheral immune phenotypes to disease progression in patients. By integrating these innovative techniques, this research aims to uncover how peripheral immune cells contribute to the onset and progression of PD, potentially identifying new biomarkers and therapeutic targets for early intervention. Modifying immune cells in the blood to modulate the brain's immune environment represents a major shift in treating PD as a multisystem neuroimmune disorder.