Fig. 8: Model for the synchronized LLPS and LSPT-driven amyloid hetero-aggregation of αS and Tau441.

The schematic shows the proposed amyloid aggregation pathway for αS and Tau441 through LLPS and LSPT. With complementary anion-rich (red) and cation-rich (blue) regions, αS and Tau electrostatic coacervates with satisfied valences have a lower surface energy and thus coalesce to a lesser extent, allowing the droplet to age rapidly reaching a stable, non-coalescing gel-like state. This situation is highly favorable in the case of the αS/pLK system owed to a higher affinity and simpler one-pair protein interaction network, which allows for a rapid gel-like transition. In contrast, droplets with unsatisfied valences and, thus, interaction-available protein charged regions, will make the coacervates more prone to coalesce and wet hydrophilic surfaces in order to reduce their high surface energy. This situation is preferred in the αS/Tau441 coacervates, which have a multivalent complex network composed of Tau-Tau and αS-Tau weak interactions. Larger coacervates, in turn, will be more susceptible to retain their liquid-like properties, allowing for other protein-protein interactions to occur. Eventually, amyloid hetero-aggregates containing both αS and Tau are formed within the liquid coacervates, which might be related to those found in neurodegenerative disease-hallmark inclusions.