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

Misfolded alpha-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson's disease (PD). A large body of evidence shows that alpha-synuclein can aggregate into amyloid fibrils, but the relationship between alpha-synuclein self-assembly and Lewy body formation remains unclear. Here, we show, both in vitro and in a Caenorhabditis elegans model of PD, that alpha-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.

Automated summary

The study demonstrates that alpha-synuclein undergoes liquid-liquid phase separation to form liquid droplets, which then convert into an amyloid-rich hydrogel with Lewy-body-like properties. However, this maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro.