Multiscale assessment of the amyloid assembly of MICRObiota-associated Bap proteins and the intermolecular templating of alpha-SYNuclein fibrils

The global rise in Parkinson’s disease (PD) and other neurodegenerative disorders is becoming an important public health concern in the European Union and worldwide. Recent discoveries have revealed a direct connection between biofilm-associated proteins (Baps) from the human microbiota and alpha-synuclein (alpha-Syn) aggregation - a pathological hallmark of PD - supporting the hypothesis that the gastrointestinal tract plays a role in the pathogenesis of neurodegenerative diseases. The MICROSYN project aims to investigate the molecular mechanisms behind the impact of Bap proteins - BapSa from Staphylococcus aureus and Esp from Enterococcus faecalis - on the aberrant assembly of alpha-Syn. Currently, structural models of BapSa and Esp amyloid fibrils and the intermolecular interactions during the templating of alpha-Syn aggregation are unknown. Utilizing the state-of-the art techniques magic angle spinning solid-state nuclear magnetic resonance and atomic force microscopy, this project will provide atomic-level information on Bap and Esp amyloid fibril structure and dynamics, reveal conformational changes upon cross-seeding with alpha-Syn, and offer valuable insights into the fibril architectures at the mesoscopic scale. This will be achieved through the expertise of Dr. Álvarez-Mena in the biochemistry and molecular biology of bacterial amyloids, combined with the host lab know-how in solid-state NMR, AFM and complementary physico-chemical techniques, supported by the cutting-edge facilities of the host institution.Understanding the interaction between microbiota-derived BapSa/Esp and human alpha-Syn will offer new therapeutic avenues for combating PD, while insights into the structures of BapSa and Esp fibrils will aid in developing antimicrobial and antibiofilm agents to tackle antibiotic resistance. Thus, the MICROSYN project will support EU health priorities by fostering innovation in disease prevention and treatment.