Dual roles of condensates in protein misfolding and aggregation.

Abstract

Protein aggregation is a hallmark in several neurodegenerative diseases, in which proteins assemble into structurally diverse misfolded states, ranging from amorphous aggregates to amyloid fibrils. Several aggregation-prone proteins can undergo phase separation to form biomolecular condensates, creating distinct chemical environments compared to the surrounding dilute phase. These environments dictate protein conformations, interaction networks, and free energy landscapes, thereby modulating aggregation pathways. Notably, condensates exert dual and context-dependent effects: they can promote aggregation by stabilizing misfolded intermediates and facilitating assembly, or they can suppress aggregation by buffering interactions and retaining proteins. Here, we summarize the current literature and describe biomolecular condensates as key regulators of protein misfolding and aggregation and highlight the importance of the local milieu in determining aggregation outcomes.