Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.17.254508v1?rss=1 Authors: Yang, X., Wang, B., Hoop, C. L., Williams, J. K., Baum, J. Abstract: Amyloid fibril formation of -synuclein (S) is associated with multiple neurodegenerative diseases, including Parkinson's Disease (PD). Growing evidence suggests that progression of PD is linked to cell-to-cell propagation of S fibrils, which leads to templated seeding of endogenous intrinsically disordered monomer. A molecular understanding of the seeding mechanism and driving interactions is crucial to inhibit progression of amyloid formation. Here, using relaxation-based solution NMR experiments designed to probe large complexes, we identify weak interactions of intrinsically disordered acetylated-S (Ac-S) monomers with seeding-competent Ac-S fibrils and seeding-incompetent off-pathway oligomers to elucidate amyloid promoting interactions at the atomic level. We identify a binding interface in the first 11 residues of the N-terminus that interacts with both fibrils and off-pathway oligomers, under conditions that favor fibril elongation. This common N-terminal hotspot is supported by suppression of seeded amyloid formation by oligomers, as observed through thioflavin-T fluorescence experiments, suggesting competing monomer interactions. This highlights that an amyloid-incompetent species of S itself can act as an auto-inhibitor against S fibril elongation. The similarity between the fibril and oligomer structures lies in their intrinsically disordered termini. Thus, we propose that the monomer-aggregate interactions occur between the intrinsically disordered monomer N-terminus and the intrinsically disordered regions (IDRs) of the fibril/oligomers. Taken together, we propose a novel Ac-S seeding mechanism that is driven by the recruitment of intrinsically disordered monomers by the fibril IDRs, highlighting the potential of the terminal IDRs of the fibril rather than the structured core, as new therapeutic targets against seeded amyloid formation. Copy rights belong to original authors. Visit the link for more info