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Liquid-liquid phase separation and liquid-to-solid transition mediate α-synuclein amyloid fibril containing hydrogel formation

Authors :
Jaladhar Mahato
Rakesh Kumar
Soumik Ray
Sushil Kumar Pandey
Siddhartha Maiti
Ranjith Padinhateeri
Amrendra K. Singh
Samir K. Maji
G. Krishnamoorthy
Juan Gerez
Debalina Datta
Ambuja Navalkar
Laxmikant G. Gadhe
Rajlaxmi Panigrahi
Surabhi Mehra
Ashutosh Kumar
Debdeep Chatterjee
Komal Patel
Nitu Singh
Sandhya Bhatia
Roland Riek
Arindrajit Chowdhury
Publication Year :
2019
Publisher :
Cold Spring Harbor Laboratory, 2019.

Abstract

SUMMARYα-Synuclein (α-Syn) aggregation and amyloid formation is directly linked with Parkinson’s disease (PD) pathogenesis. However, the early events involved in this process remain unclear. Here, using in vitro reconstitution and cellular model, we show that liquid-liquid phase separation (LLPS) 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 amyloid-hydrogel containing oligomers and fibrillar species. Factors known to aggravate α-Syn aggregation such as low pH, phosphomimic substitution, and familial PD mutation also promote α-Syn LLPS and its subsequent maturation. We further demonstrate α-Syn liquid droplet formation in cells, under oxidative stress. These cellular α-Syn droplets eventually transform into perinuclear aggresomes, the process regulated by microtubules. The present work provides detailed insights into the phase separation behavior of natively unstructured α-Syn and its conversion to a disease-associated aggregated state, which is highly relevant in PD pathogenesis.

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....6cc13e24524b2e0424e74a620fd3467a
Full Text :
https://doi.org/10.1101/619858