A global thermodynamic-kinetic model capturing the hallmarks of liquid-liquid phase separation and amyloid...

Amyloid aggregation is associated with numerous neurodegenerative, systemic, and metabolic diseases. Amyloidogenic proteins often undergo liquid-liquid phase separation (LLPS), but the effects of LLPS on amyloid aggregation remain unclear, as contrasting fibrillization promotion and inhibition and even biphasic effects have been reported. Here, we adopt the phase-transition theory and integrate LLPS-induced heterogeneity of protein concentrations into a thermodynamic-kinetic model of aggregation. Oligomerization and fibrillization can occur both in the protein-rich condensates and the protein-poor solution. This model allows us to derive the time evolution of different states-monomers, condensates, oligomers, and fibrils-spanning a wide concentration range, and to determine how parameters governing LLPS, fibrillization, and oligomerization influence fibrillization kinetics, thereby capturing the contrasting features of LLPS driven by either monomers or oligomers. In sum, this global model reconciles the seemingly contradictory effects of LLPS on fibrillization and advances our understanding, modulation, and potential mitigation of pathological aggregation in amyloid diseases.