The chemistry of structural proteins in the lens of the eye changes with age in ways that render the lens less flexible, contributing to vision issues such as presbyopia, and eventually degrade its transparency. Age-related cataracts are the outcome of chemical alterations that cloud the lens and eventually lead to blindness. Better understanding the chemistry involved in this loss of transparency should hopefully lead to ways to replace the problematic molecular structures, or at least help to prevent the early stages of their formation. This is more challenging for the lens of the eye than is the case for most tissues that become damaged with age, as there is at best very limited natural replacement of the structural proteins of the lens. At present, replacement approaches are focused on surgery to replace the lens rather than any sort of nanoscale, chemical intervention that preserves the existing tissue.
The human eye lens plays an essential role in vision by focusing light onto the retina. This transparent tissue consists of densely packed crystallin proteins that exhibit remarkable solubility despite minimal protein turnover. Unlike most proteins, which are continuously recycled, crystallins must remain stable and soluble throughout the human lifespan. Aging causes damage to the lens, primarily via photochemical oxidation. Over time, this causes crystallin aggregation and leads to cataract.
Although understanding oxidative damage is critical to understanding cataract formation and how it can be prevented, it is difficult to study in native biological systems. Here, we use genetic code expansion to introduce an oxidation product, 5-hydroxytryptophan (5HTP), in a key site in human γS-crystallin, enabling it to be specifically investigated under controlled conditions. Replacing a critical tryptophan residue with 5HTP leads to reduced stability and increased aggregation.
