Heterotypic phase separation in aggregation: Driver or deterrent?

Liquid–liquid phase separation (LLPS) of proteins implicated in neurodegenerative diseases has gained growing attention in recent years, due to its potential role in driving the transition from functional protein monomers to pathogenic aggregates. However, the mechanisms by which phase separation contributes to the loss of protein function and promotes aggregation remain poorly understood. Recent studies show that multiple proteins or other biomolecules can colocalize within the biomolecular condensates, creating a highly interactive microenvironment that can modulate aggregation. In this review we look into the heterotypic phase separation of tau and α-synuclein, the two key proteins responsible for critical neurodegenerative disorders. By compiling recent findings, this review highlights the modulatory role of heterotypic condensates in disease progression and aims to provide an alternative perspective on regulation of protein aggregation in neurodegeneration. • Heterotypic LLPS modulates condensation and aggregation of tau and α-synuclein. • LLPS partners are classified by effects on condensate dynamics and aggregation. • Chaperones redirect condensation pathways and suppress tau aggregation. • Most amyloidogenic co-partners enhance LLPS and drive aggregation. • Targeting heterotypic LLPS offers strategies to mitigate neurodegeneration.