Spatial control of irreversible protein aggregation

TL;DR

This study combines kinetic theory and phase separation to understand how liquid cellular compartments influence the spatial distribution and enrichment of irreversible protein aggregates, with implications for disease mechanisms.

Contribution

It introduces a model linking phase separation with protein aggregation, revealing how compartments can concentrate aggregates through a feedback mechanism.

Findings

Aggregates are enriched inside liquid compartments even with weak interactions.

Enrichment is driven by a feedback mechanism involving nucleation and growth.

The optimal compartment volume depends on the reaction order of nucleation.

Abstract

Liquid cellular compartments spatially segregate from the cytoplasm and can regulate aberrant protein aggregation, a process linked to several medical conditions, including Alzheimer's and Parkinson's diseases. Yet the mechanisms by which these droplet-like compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid compartments. We find that, even for weak interactions between the compartment constituents and the aggregating monomers, aggregates are strongly enriched inside the liquid compartment relative to the surrounding cytoplasm. We show that this enrichment is caused by a positive feedback mechanism of aggregate nucleation and growth which is mediated by a flux maintaining the phase equilibrium between the compartment and the cytoplasm. Our model predicts that the compartment volume that maximizes aggregate enrichment in the compartment is determined by the reaction orders of aggregate nucleation. The underlying mechanism of aggregate enrichment could be used to confine cytotoxic protein aggregates inside droplet-like compartments suggesting potential new avenues against aberrant protein aggregation. Our findings could also represent a common mechanism for the spatial control of irreversible chemical reactions in general.