Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies.
Hardenberg, Maarten C
Dada, Samuel T
Robinson, Elizabeth A
Kaminksi, Clemens F
Nollen, Ellen AA
Dobson, Christopher M
Journal of molecular cell biology
Oxford University Press (OUP)
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Hardenberg, M. C., Sinnige, T., Casford, S., Dada, S. T., Poudel, C., Robinson, E. A., Fuxreiter, M., et al. (2021). Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies.. Journal of molecular cell biology, 13 (4), 282-294. https://doi.org/10.1093/jmcb/mjaa075
Misfolded a-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson’s disease. A large body of evidence shows that a-synuclein can aggregate into amyloid fibrils, but the relationship between a-synuclein self-assembly and Lewy body formation remains unclear. Here we show, both in vitro and in a C. elegans model of Parkinson’s disease, that a-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 a-synuclein condensates in the presence of lipids and other cellular components.
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.
Wellcome Trust (065807/Z/01/Z)
Wellcome Trust (203249/Z/16/Z)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (722380)
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External DOI: https://doi.org/10.1093/jmcb/mjaa075
This record's URL: https://www.repository.cam.ac.uk/handle/1810/315115
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