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bioRxiv · 10.1101/2020.06.08.140798

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

Hardenberg, M. C.·Sinnige, T.·Casford, S.·Dada, S.·Poudel, C.·Robinson, L.·Fuxreiter, M.·Kaminski, C. F.·Kaminski Schierle, G. S.·Nollen, E. A. A.·Dobson, C. M.·Vendruscolo, M.
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Abstract

Misfolded -synuclein is a major component of Lewy bodies, which are a hallmark of Parkinsons disease. A large body of evidence shows that -synuclein can self-assemble into amyloid fibrils, but the relationship between amyloid formation and Lewy body formation still remains unclear. Here we show, both in vitro and in a C. elegans model of Parkinsons disease, that -synuclein undergoes liquid-liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel. 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 is linked to the arrested maturation of -synuclein condensates in the presence of lipids and other cellular components.

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Hardenberg, M. C., Sinnige, T., Casford, S., Dada, S., Poudel, C., Robinson, L., Fuxreiter, M., Kaminski, C. F., Kaminski Schierle, G. S., Nollen, E. A. A., Dobson, C. M., Vendruscolo, M.. 2020-06-09. Observation of an α-synuclein liquid droplet state and its maturation into Lewy body-like assemblies. https://doi.org/10.1101/2020.06.08.140798

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