Liquid-Liquid Phase Separation (LLPS) describes the spontaneous separation of a homogeneous protein solution into two phases: a dense phase enriched with biomolecules and a solution phase depleted of them, exhibiting differing physical properties such as viscosity and diffusivity. Some of the physiological or pathological condensates include nucleoli, promyelocytic leukemia (PML) nuclear bodies, and stress granules. These condensates are liquid-like, with composite biomolecules forming a network facilitated by weak and dynamic intermolecular interactions. Increasing experimental studies showed that amyloid proteins, including amyloid-β (Aβ), α-synuclein, tau, islet amyloid polypeptide (IAPP), insulin A-chain fragment, and TDP-43, can undergo LLPS and form condensates. The condensates, usually assume the morphology of spheres and are often referred to as “droplets” in literature, provide the temporal and spatial organizations of amyloid proteins.
LLPS-driven condensates not only serve as dynamic compartments within the cell but may also act as potent modulators of amyloid aggregation kinetics. It has been postulated that the elevated concentration of amyloidogenic proteins within these condensates could promote the formation of toxic oligomers and enhance nucleation rates, facilitating the formation of amyloid fibrils. On the other hand, some other experimental studies showed that the formation of condensates could significantly hinder or delay the nucleation and growth of amyloid fibrils. Hence, the effect of protein condensate formation via LLPS on amyloid aggregation is likely complex. Understanding both LLPS and amyloid aggregation, as well as their interplay, is an active area of research with potential implications for the development of therapeutic interventions for neurodegenerative diseases and other amyloid-related disorders.
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