Probing acetylated-α-synuclein monomer-aggregate complexes by NMR elucidates mechanism of fibril seeding

摘要: Amyloid fibril formation of -synuclein (S) is associated with multiple neurodegenerative diseases, including Parkinsons Disease (PD). Growing evidence suggests that progression PD linked to cell-to-cell propagation S fibrils, which leads templated seeding endogenous intrinsically disordered monomer. A molecular understanding the mechanism and driving interactions crucial inhibit amyloid formation. Here, using relaxation-based solution NMR experiments designed probe large complexes, we identify weak acetylated-S (Ac-S) monomers seeding-competent Ac-S fibrils seeding-incompetent off-pathway oligomers elucidate promoting at atomic level. We a binding interface in first 11 residues N-terminus interacts both oligomers, under conditions favor elongation. This common N-terminal hotspot supported by suppression seeded as observed through thioflavin-T fluorescence experiments, suggesting competing monomer interactions. highlights an amyloid-incompetent species itself can act auto-inhibitor against The similarity between oligomer structures lies their termini. Thus, propose monomer-aggregate occur regions (IDRs) fibril/oligomers. Taken together, novel driven recruitment IDRs, highlighting potential terminal IDRs rather than structured core, new therapeutic targets SignificanceCell-to-cell spreading detailed atomic-level mechanistic process essential for design approaches disease. In light its complexity, this remains ill-defined Using are able map acetylated critical early late stages aggregation. From work, paradigm, initiated N- C-termini on surface, may provide