α-Synuclein oligomers form by secondary nucleation

Catherine K. Xu, Georg Meisl, Ewa A. Andrzejewska, Georg Krainer, Alexander J. Dear, Marta Castellana-Cruz, Soma Turi, Irina A. Edu, Giorgio Vivacqua, Raphaël P. B. Jacquat, William E. Arter, Maria Grazia Spillantini, Michele Vendruscolo, Sara Linse and Tuomas P. J. Knowles ()
Additional contact information
Catherine K. Xu: University of Cambridge
Georg Meisl: University of Cambridge
Ewa A. Andrzejewska: University of Cambridge
Georg Krainer: University of Cambridge
Alexander J. Dear: University of Cambridge
Marta Castellana-Cruz: University of Cambridge
Soma Turi: University of Cambridge
Irina A. Edu: University of Cambridge
Giorgio Vivacqua: Campus Biomedico University of Rome
Raphaël P. B. Jacquat: University of Cambridge
William E. Arter: University of Cambridge
Maria Grazia Spillantini: University of Cambridge
Michele Vendruscolo: University of Cambridge
Sara Linse: Lund University
Tuomas P. J. Knowles: University of Cambridge

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Oligomeric species arising during the aggregation of α-synuclein are implicated as a major source of toxicity in Parkinson’s disease, and thus a major potential drug target. However, both their mechanism of formation and role in aggregation are largely unresolved. Here we show that, at physiological pH and in the absence of lipid membranes, α-synuclein aggregates form by secondary nucleation, rather than simple primary nucleation, and that this process is enhanced by agitation. Moreover, using a combination of single molecule and bulk level techniques, we identify secondary nucleation on the surfaces of existing fibrils, rather than formation directly from monomers, as the dominant source of oligomers. Our results highlight secondary nucleation as not only the key source of oligomers, but also the main mechanism of aggregate formation, and show that these processes take place under conditions which recapitulate the neutral pH and ionic strength of the cytosol.

Date: 2024
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DOI: 10.1038/s41467-024-50692-4

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