Melatonin, ATP, and Cataracts: The Two Faces of Crystallin Phase Separation

Abstract

The high concentration of crystallin proteins in the lens maintains transparency and clarity via a high refractive index that ensures optical quality. The chaperone-like activity of crystallins protects lenses against damaging protein aggregation and misfolding. The highly-crowded molecular environment in the lens fosters dehydration entropy-driven phase separation of crystallin proteins that can be activated by changes in temperature, ion and salt concentrations; and exposure to endogenous and exogenous stress including reactive oxygen species (ROS) and ultraviolet radiation. The sensitive balance between melatonin and adenosine triphosphate (ATP) prevents amorphous crystallin condensates from transitioning into amyloidogenic fibrillar aggregates present in late-stage cataracts. Melatonin exerts a multi-pronged strategy against cataractogenesis: first by scavenging ROS at condensate redox-reactive interfaces, effectively preventing the removal of water molecules from protein hydration shells that can cause the formation of pathogenic amyloid fibrils, then by complementing the ability of ATP to solubilize and disassemble protein aggregates via the adenosine moiety. Melatonin and ATP together strengthen hydrogen bonding, ensuring the proper ratio of bound water to free water, thereby preventing aberrant phase separation of crystallins and cataractogenesis. The progression of cataracts and glaucoma may be a reflection of an age-related decline in the production of melatonin and ATP exacerbated by exposure to light at night. Targeting this powerful, ancient synergy between melatonin and ATP offers an efficacious solution for ocular diseases driven by phase separation.