Researchers at the University of California, Irvine have identified a chemical change in an eye lens protein that may play a role in the early stages of cataract formation. The study, published in Biophysical Reports, examines how age-related modifications to proteins called crystallins can increase their tendency to clump together, which is linked to cataracts.
Crystallins are essential for maintaining lens clarity throughout life. Unlike most cells, the lens cannot replace damaged proteins, so changes accumulate over time. Age-related cataracts—the most common type—are not primarily caused by genetics but develop gradually due to environmental factors like ultraviolet (UV) light exposure. UV light can cause chemical stress and damage crystallin proteins.
To investigate this process, the research team used genetic code expansion (GCE), a technique that allows for precise changes to be made to proteins. "GCE lets us make very precise changes to a protein," said Seo, one of the researchers. "We used it to copy one kind of damage that shows up in age-related cataracts and see exactly what it does."
The team introduced an oxidative modification at a specific site on γS-crystallin, a lens protein. Although the modified protein remained stable under normal conditions, it was more prone to clumping when exposed to heat compared with its unmodified counterpart.
"The protein doesn't fall apart right away," Seo explained. "It just becomes a little more likely to interact with its neighbors, and over time that can lead to clumping."
Seo's group is now examining how oxidation affects the natural movements of these proteins. Subtle shifts in structure may expose regions normally protected from interaction.
"We're essentially watching how the protein breathes," said Seo. "If certain parts start moving more than they should, it can briefly open up areas that are normally protected."
By linking age-related oxidation with altered protein motion, the researchers aim to understand how defenses against clumping weaken as people age. Their findings could help guide efforts toward preventing or delaying cataract development.
"Almost everyone who lives long enough will get age-related cataracts," said Rachel Martin, UC Irvine professor of chemistry and corresponding author on the study. "GCE enables us to study specific changes that happen with proteins in the aging lens, furthering our understanding of what causes cataracts at the molecular level. Understanding the loss of function that comes with aging could lead to non-surgical treatments or improved artificial lenses in the future."
Key contributors include UC Irvine alumni Zane Long, Tsoler Demerdjian, Acts Avenido; Professor Carter T. Butts; and Professor Rachel W. Martin’s laboratory conducted the experimental work. Funding came from National Institutes of Health grants R01GM144964 (to C.T.B and R.W.M.) and R01EY021514 (to R.W.M.).
