α-Synuclein aggregation nucleates through liquid–liquid phase separation

By S. Ray, Nitu Singh, Rakesh Kumar, Komal Patel, Satyaprakash Pandey, Debalina Datta, Jaladhar Mahato, R. Panigrahi, Ambuja Navalkar, Surabhi Mehra and 12 more. Nature Chemistry, 2020

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α-Synuclein (α-Syn) aggregation and amyloid formation is directly linked with Parkinson’s disease pathogenesis. However, the early events involved in this process remain unclear. Here, using the in vitro reconstitution and cellular model, we show that liquid–liquid phase separation of α-Syn precedes its aggregation. In particular, in vitro generated α-Syn liquid-like droplets eventually undergo a liquid-to-solid transition and form an amyloid hydrogel that contains oligomers and fibrillar species. Factors known to aggravate α-Syn aggregation, such as low pH, phosphomimetic substitution and familial Parkinson’s disease mutations, also promote α-Syn liquid–liquid phase separation and its subsequent maturation. We further demonstrate α-Syn liquid-droplet formation in cells . These cellular α-Syn droplets eventually transform into perinuclear aggresomes, the process regulated by microtubules. This work provides detailed insights into the phase-separation behaviour of natively unstructured α-Syn and its conversion to a disease-associated aggregated state, which is highly relevant in Parkinson’s disease pathogenesis. The mechanism of nucleation for α-synuclein (α-Syn) aggregation and amyloid formation in Parkinson’s disease is unclear. Now, α-Syn has been shown to undergo liquid–liquid phase separation and a liquid-to-solid-like transition leading to amyloid fibril formation. This raises the possibility that liquid–liquid phase separation is a key pathogenic mechanism behind α-Syn aggregation in Parkinson’s disease.

Subfields: Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/ee4a043cabda48a5c21ac99901e7875f258297d4