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

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Zhang, Yu P 
Lobanova, Evgeniia 
Miller, Alyssa 


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.


Funder: Royal Society


Brain, Humans, Liposomes, Parkinson Disease, Protein Aggregates, alpha-Synuclein

Journal Title

Nat Commun

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Nature Research
Parkinson's UK (G-1901)
European Research Council (669237)
Engineering and Physical Sciences Research Council (EP/R005397/1)
Medical Research Council (MR/R007446/1)
Engineering and Physical Sciences Research Council (EP/P008224/1)
This work was supported by Parkinson’s UK (G-1901), UK Dementia Research Institute, which receives its funding from DRI Ltd. funded by the UK Medical Research Council and by the European Research Council Grant Number 669237 and the Royal Society. Y.Z .was supported by the UK Engineering and Physical Sciences Research Council (EP/R005397/1) and the NIHR Cambridge Biomedical Research Centre Dementia and Neurodegeneration Theme (146281).