Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau

Pablo Gracia, David Polanco, Jorge Tarancón-Díez, Ilenia Serra, Maruan Bracci, Javier Oroz, Douglas V. Laurents, Inés García and Nunilo Cremades ()
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Pablo Gracia: University of Zaragoza
David Polanco: University of Zaragoza
Jorge Tarancón-Díez: University of Zaragoza
Ilenia Serra: University of Zaragoza
Maruan Bracci: University of Zaragoza
Javier Oroz: “Rocasolano” Institute for Physical Chemistry, CSIC
Douglas V. Laurents: “Rocasolano” Institute for Physical Chemistry, CSIC
Inés García: University of Zaragoza
Nunilo Cremades: University of Zaragoza

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Amyloid aggregation of α-synuclein (αS) is the hallmark of Parkinson’s disease and other synucleinopathies. Recently, Tau protein, generally associated with Alzheimer’s disease, has been linked to αS pathology and observed to co-localize in αS-rich disease inclusions, although the molecular mechanisms for the co-aggregation of both proteins remain elusive. We report here that αS phase-separates into liquid condensates by electrostatic complex coacervation with positively charged polypeptides such as Tau. Condensates undergo either fast gelation or coalescence followed by slow amyloid aggregation depending on the affinity of αS for the poly-cation and the rate of valence exhaustion of the condensate network. By combining a set of advanced biophysical techniques, we have been able to characterize αS/Tau liquid-liquid phase separation and identified key factors that lead to the formation of hetero-aggregates containing both proteins in the interior of the liquid protein condensates.

Date: 2022
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DOI: 10.1038/s41467-022-32350-9

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