Inhibition and Formation of Amyloid Fibrils in the Bulk and at the Interface of Biomolecular Condensates

ABSTRACT Cells can form open compartments, known as biomolecular condensates, which possess distinct environments and concentrations compared to their surroundings. These biomolecular condensates can modulate biochemical processes, including protein aggregation. Notably, they have been reported to both accelerate and inhibit protein aggregation. Since protein aggregation is often associated with pathological conditions like neurodegenerative diseases, it is crucial to understand the molecular mechanisms underlying the interplay between phase separation and fibril formation. In this review, we discuss how, contrary to intuition, aggregation within the bulk of condensates can be inhibited rather than promoted, even in the presence of elevated local protein concentration. However, biomolecular condensates can still facilitate fibril formation by generating an interface between the dense and dilute phases, where molecular and mesoscale properties are optimal for the nucleation of protein aggregation.