Yeonseong (Catherine) Seo, Ph.D. candidate in Chemistry at UC Irvine, conducts protein unfolding experiments to probe how subtle chemical changes affect protein stability.
Photo Credit: Lucas Van Wyk Joel / UC Irvine
Scientific Frontline: Extended "At a Glance" Summary: Molecular Origins of Age-Related Cataracts
The Core Concept: Age-related cataracts begin when subtle oxidative chemical changes accumulate in eye lens proteins over decades, causing the proteins to stick together and progressively cloud the lens.
Key Distinction/Mechanism: Unlike most cells in the human body, the eye lens cannot replace damaged proteins. Prolonged environmental stress, primarily from ultraviolet (UV) light, induces mild oxidative modifications in a specific lens protein called γS-crystallin. While the protein remains mostly stable and folded, this subtle chemical damage increases its propensity to interact and clump with neighboring proteins when exposed to stress, such as heat.
Major Frameworks/Components:
- Crystallins (γS-crystallin): The highly stable structural proteins responsible for maintaining the transparency of the eye lens over a human lifespan.
- Oxidative Stress: Environmental damage (e.g., UV exposure) that alters the chemical structure of proteins without destroying them entirely.
- Genetic Code Expansion (GCE): A biochemical tool utilized by researchers to synthesize proteins with exact, engineered chemical modifications, allowing for the precise replication of natural age-related oxidative damage in vitro.
- Protein "Breathing" (Structural Dynamics): The natural, subtle physical movements of protein molecules. Researchers hypothesize that oxidation alters these dynamics, briefly exposing normally protected, vulnerable regions of the protein that facilitate clumping.
Branch of Science: Biochemistry, Biophysics, Molecular Biology, and Ophthalmology.
Future Application: The findings provide a foundational understanding of age-related protein dysfunction, which could drive the development of prophylactic non-surgical treatments (such as eye drops) to slow or prevent cataract formation, as well as the engineering of improved artificial lens replacements.
Why It Matters: Cataracts are a leading cause of blindness globally, currently affecting 25 million people in the U.S. and over 65 million worldwide. As life expectancies increase, understanding the molecular onset of this condition is critical to mitigating a disease that will eventually impact almost everyone who reaches old age.
Cataracts are a leading cause of blindness worldwide and are considered a priority disease by the World Health Organization. In a new study, researchers at the University of California, Irvine uncovered how a subtle chemical change in an eye lens protein can make the protein more likely to clump together over time, suggesting an early step in cataract formation.
The research, published in Biophysical Reports, focuses on proteins called crystallins, which help keep the eye lens clear. These proteins are meant to last a lifetime. But unlike most cells in the body, the lens cannot replace damaged proteins, so chemical changes can gradually accumulate over decades.
“What surprised us is that the protein can still look mostly normal, but even a small chemical change makes it much more likely to stick to other proteins,” said lead author Yeonseong (Catherine) Seo, a UC Irvine Ph.D. candidate in chemistry. “Over time, those small interactions can add up and cloud the lens.”
The team studied age-related cataracts, the most common form of the disease. Rather than being caused by genetics, this type typically develops slowly due to environmental exposure, such as ultraviolet light from the sun. UV light creates chemical stress in the eye that can damage crystallin proteins.
To better understand how this damage affects lens proteins, the researchers turned to a tool called genetic code expansion, or GCE. This method allows scientists to build proteins with specific chemical features.
In their study, Seo and her team used the tool differently to recreate a single type of chemical change that naturally occurs in the aging eye.
“GCE lets us make very precise changes to a protein,” Seo said. “We used it to copy one kind of damage that shows up in age-related cataracts and see exactly what it does.”
Using this approach, the researchers introduced a small oxidative change at one specific location in a lens protein called γS-crystallin. Even with this modification, the protein remained folded and stable. But when stressed by heat, it clumped together much more easily than the unmodified version.
“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 and her team are now investigating why this happens by studying how oxidation affects the natural movement of these proteins. Proteins are not rigid structures, and their subtle motions help keep vulnerable regions safely tucked away.
“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 connecting age-related oxidation to changes in protein motion, the researchers hope to better understand how the eye’s natural defenses against protein clumping gradually weaken with age. This work moves researchers one step closer to finding ways to slow or prevent cataracts before it affects vision.
“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.”
Funding: The experimental work was performed in the lab of Rachel W. Martin. Key sources of funding include the National Institutes of Health under award numbers R01GM144964 to C.T.B. and R.W.M. and R01EY021514 to R.W.M.
Published in journal: Biophysical Reports
Title: Mimicking oxidative damage in γS-crystallin with site-specific incorporation of 5-hydroxytryptophan
Authors: Yeonseong Seo, Zane G. Long, Tsoler K. Demerdjian, Acts A. Avenido, Carter T. Butts, and Rachel W. Martin
Source/Credit: University of California, Irvine
Reference Number: bchm030426_02
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