Small soluble α-synuclein aggregates are the toxic species in Parkinson’s disease

Derya Emin, Yu P. Zhang, Evgeniia Lobanova, Alyssa Miller, Xuecong Li, Zengjie Xia, Helen Dakin, Dimitrios I. Sideris, Jeff Y. L. Lam, Rohan T. Ranasinghe, Antonina Kouli, Yanyan Zhao, Suman De, Tuomas P. J. Knowles, Michele Vendruscolo, Francesco S. Ruggeri, Franklin I. Aigbirhio, Caroline H. Williams-Gray and David Klenerman ()
Additional contact information
Derya Emin: University of Cambridge
Yu P. Zhang: University of Cambridge
Evgeniia Lobanova: University of Cambridge
Alyssa Miller: University of Cambridge
Xuecong Li: Wageningen University and Research
Zengjie Xia: University of Cambridge
Helen Dakin: University of Cambridge
Dimitrios I. Sideris: University of Cambridge
Jeff Y. L. Lam: University of Cambridge
Rohan T. Ranasinghe: University of Cambridge
Antonina Kouli: University of Cambridge
Yanyan Zhao: University of Cambridge
Suman De: University of Cambridge
Tuomas P. J. Knowles: University of Cambridge
Michele Vendruscolo: University of Cambridge
Francesco S. Ruggeri: University of Cambridge
Franklin I. Aigbirhio: University of Cambridge
Caroline H. Williams-Gray: University of Cambridge
David Klenerman: University of Cambridge

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Soluble α-synuclein aggregates varying in size, structure, and morphology have been closely linked to neuronal death in Parkinson’s disease. However, the heterogeneity of different co-existing aggregate species makes it hard to isolate and study their individual toxic properties. Here, we show a reliable non-perturbative method to separate a heterogeneous mixture of protein aggregates by size. We find that aggregates of wild-type α-synuclein smaller than 200 nm in length, formed during an in vitro aggregation reaction, cause inflammation and permeabilization of single-liposome membranes and that larger aggregates are less toxic. Studying soluble aggregates extracted from post-mortem human brains also reveals that these aggregates are similar in size and structure to the smaller aggregates formed in aggregation reactions in the test tube. Furthermore, we find that the soluble aggregates present in Parkinson’s disease brains are smaller, largely less than 100 nm, and more inflammatory compared to the larger aggregates present in control brains. This study suggests that the small non-fibrillar α-synuclein aggregates are the critical species driving neuroinflammation and disease progression.

Date: 2022
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DOI: 10.1038/s41467-022-33252-6

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