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Electrostatically Driven Complex Coacervation and Amyloid Aggregation of Tau Are Independent Processes with Overlapping Conditions.

ACS chemical neuroscience (2020-01-24)
Yanxian Lin, Yann Fichou, Zhikai Zeng, Nicole Y Hu, Songi Han
ABSTRACT

Amyloid aggregation of the microtubule binding protein tau is a hallmark of many neurodegenerative diseases. Recently, tau has been found to undergo liquid-liquid phase separation (LLPS) by an electrostatically driven complex coacervation (CC) mechanism near physiological conditions. Although LLPS and aggregation have been shown to simultaneously occur under certain common conditions, it is unclear whether LLPS promotes aggregation of tau, or whether they are two independent processes. In this study, we address this question by combining multiple biochemical and biophysical assays in vitro. We investigate the impacts of LLPS-CC on cofactor-induced tau aggregation by evaluating the conformation of tau, kinetics of aggregation, and fibril quantity. We showed that none of these properties are influenced directly by LLPS-CC and that LLPS-CC and cofactor-induced aggregation of tau merely occur under overlapping conditions of enhanced intermolecular interactions and localization but are two independent processes. We furthermore showed that tau LLPS can be driven by nonelectrostatic interaction using high-salt concentrations. Under these conditions, LLPS strongly correlated with increased aggregation propensity. Whether LLPS of tau formed under different conditions or of different constituents may actively promote aggregation of tau remains an open question, but this study shows that the readily accessible electrostatically driven condensation of tau into LLPS in and of itself is not sufficient to promote aggregation.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Deoxyribonuclease I from bovine pancreas, lyophilized powder, Protein ≥85 %, ≥400 Kunitz units/mg protein
Sigma-Aldrich
LB Broth (Lennox), Highly-referenced microbial growth powder medium, low salt, suitable for salt-sensitive E.coli culture.
Sigma-Aldrich
poly(A)
Sigma-Aldrich
Polyuridylic acid potassium salt
Sigma-Aldrich
Hyaluronic acid sodium salt from Streptococcus equi, mol wt 8,000-15,000