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Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies.

Accepted version
Peer-reviewed

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Article

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Authors

Hardenberg, Maarten C 
Sinnige, Tessa 
Casford, Sam 
Dada, Samuel T 
Poudel, Chetan 

Abstract

Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson's disease (PD). A large body of evidence shows that α-synuclein can aggregate into amyloid fibrils, but the relationship between α-synuclein self-assembly and Lewy body formation remains unclear. Here, we show, both in vitro and in a Caenorhabditis elegans model of PD, that α-synuclein undergoes liquid‒liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel with Lewy-body-like properties. This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro. Taken together, these results suggest that the formation of Lewy bodies may be linked to the arrested maturation of α-synuclein condensates in the presence of lipids and other cellular components.

Description

Keywords

Parkinson's disease, liquid‒liquid phase separation, α-synuclein, Animals, Animals, Genetically Modified, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Disease Models, Animal, Humans, Lewy Bodies, Parkinson Disease, alpha-Synuclein

Journal Title

J Mol Cell Biol

Conference Name

Journal ISSN

1674-2788
1759-4685

Volume Title

13

Publisher

Oxford University Press (OUP)

Rights

All rights reserved
Sponsorship
Wellcome Trust (065807/Z/01/Z)
Medical Research Council (MR/K02292X/1)
Wellcome Trust (203249/Z/16/Z)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (722380)
Biotechnology and Biological Sciences Research Council (BB/M011194/1)
Medical Research Council (G0902243)
Wellcome Trust (065807/Z/01/Z) (203249/Z/16/Z). Also, the UK Medical Research Council (MRC) (MR/K02292X/1), Alzheimer Research UK (ARUK) (ARUK-PG013-14), Michael J Fox Foundation (16238) and from Infinitus China Ltd.