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Quantifying Co-Oligomer Formation by α-Synuclein.

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Dear, Alexander J 
Garcia, Gonzalo A 
De, Suman 
Tosatto, Laura 


Small oligomers of the protein α-synuclein (αS) are highly cytotoxic species associated with Parkinson's disease (PD). In addition, αS can form co-aggregates with its mutational variants and with other proteins such as amyloid-β (Aβ) and tau, which are implicated in Alzheimer's disease. The processes of self-oligomerization and co-oligomerization of αS are, however, challenging to study quantitatively. Here, we have utilized single-molecule techniques to measure the equilibrium populations of oligomers formed in vitro by mixtures of wild-type αS with its mutational variants and with Aβ40, Aβ42, and a fragment of tau. Using a statistical mechanical model, we find that co-oligomer formation is generally more favorable than self-oligomer formation at equilibrium. Furthermore, self-oligomers more potently disrupt lipid membranes than do co-oligomers. However, this difference is sometimes outweighed by the greater formation propensity of co-oligomers when multiple proteins coexist. Our results suggest that co-oligomer formation may be important in PD and related neurodegenerative diseases.



cross-aggregation, mixed oligomers, neurodegeneration, oligomer toxicity, single-molecule fluorescence, statistical mechanical modeling, Amyloid beta-Peptides, Humans, Models, Molecular, Thermodynamics, alpha-Synuclein, tau Proteins

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ACS Nano

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American Chemical Society (ACS)
European Research Council (669237)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (701013)
The authors are grateful for financial support provided by Dr Tayyeb Hussain Scholarship and the ERC (669237) (M. Iljina), the Schiff Foundation (A. Dear), Alzheimer’s Research UK and Marie-Curie Individual Fellowship (S. De), a fellowship from Fondazione Caritro, Trento (BANDO 2017 PER PROGETTI DI RICERCA SVOLTI DA GIOVANI RICERCATORI POST-DOC) (L. Tosatto), the Boehringer Ingelheim Fonds and the Studienstiftung des deutschen Volkes (P. Flagmeier), the Centre for Misfolding Diseases (A. Dear, P. Flagmeier, C. Dobson, T. Knowles), the ERC (669237) and the Royal Society (D. Klenerman). We are grateful to S. Preet for the expression and purification of A90C ɑS. We thank Y. Ye for providing tau k18.