Quantifying Co-Oligomer Formation by α-Synuclein.
Dear, Alexander J
Garcia, Gonzalo A
Whiten, Daniel R
American Chemical Society (ACS)
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Iljina, M., Dear, A. J., Garcia, G. A., De, S., Tosatto, L., Flagmeier, P., Whiten, D. R., et al. (2018). Quantifying Co-Oligomer Formation by α-Synuclein.. ACS nano, 12 (11), 10855-10866. https://doi.org/10.1021/acsnano.8b03575
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-beta (Aβ) and tau, 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 co-oligomers. However, this difference is sometimes outweighed by the greater formation propensity of co-oligomers when multiple proteins co-exist. Our results suggest that co-oligomer formation may be important in PD and related neurodegenerative diseases.
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.
European Research Council (669237)
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External DOI: https://doi.org/10.1021/acsnano.8b03575
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286525