PhD Defence Jonathan Vaneyck | Transmission of the amyloid fold between alpha-Synuclein and other protein species

Transmission of the amyloid fold between alpha-Synuclein and other protein species

Jonathan Vaneyck is a PhD student in the Department of Nanobiophysics. (Co)Promotors are prof.dr. M.M.A.E. Claessens and dr. K. Broersen from the Faculty of Science & Technology.

NanobiophysicsAmyloid aggregation of α-Synuclein (aSyn) is a central pathological hallmark of synucleinopathies, including Parkinson’s disease, yet the contribution of exogenous proteins and environmental amyloids to this process remains poorly understood. This thesis investigates the transmission of the amyloid fold between aSyn and heterologous protein species by combining biophysical experiments, computational modeling, machine learning approaches, and diagnostic assay development. Using food-derived and unrelated amyloid fibrils, it is shown that heterologous cross-seeding of aSyn is highly selective and governed by specific surface-exposed physicochemical features, particularly charge patterns, rather than by amyloid structure alone. Furthermore, a supervised machine learning model based on sequence-derived descriptors successfully predicts soluble proteins capable of inducing aSyn aggregation, providing a computational framework to identify potential biological interaction partners involved in pathological aggregation. In parallel, a highly sensitive real-time quaking-induced conversion (RT-QuIC) assay was developed to detect trace amounts of aSyn aggregates in biological fluids, enabling near single-fibril sensitivity. Together, these findings support a model in which exogenous amyloids, dietary proteins, and specific protein–protein interactions may contribute to early aggregation events along the gut–brain axis, while also providing new mechanistic insights, predictive tools, and diagnostic strategies to advance the understanding and detection of amyloid-driven neurodegenerative disease processes.