September 2008




Zeroing in on peptides’ role in cataract formation

by Maxine Lipner Senior EyeWorld Contributing Editor



Investigators look to eventually stall cataracts before they begin

Intriguing new results may make it possible to one day eliminate the diminution of quality of life that results from cataract formation Source: National Eye Institute

Small peptides linked to proteins known as crystallins may be responsible for the clouding of the lens in eyes with cataracts, according to findings from a recent study published in the March 28, 2008, issue of the Journal of Biological Chemistry. These crystallin fragments may be an important key in understanding cataract formation, believes Krishna Sharma, Ph.D., professor of ophthalmology, University of Missouri, Columbia.

“Age-related modifications and oxidation and protein aggregation is what causes cataracts in at least half of the cases,” Dr. Sharma said. He sees quelling the formation of these peptides as a possible way to delay the aging process. Others had looked into the possibility that protein breakdown played a role in cataract formation, but without substantial success. “The role of protein breakdown has been on the back burner for some time, but no one really explained this,” Dr. Sharma said. “We’re the first group to focus on the peptides really playing a role in the protein aggregation.”

Anti-chaperoning properties

Investigators here first began to take a closer look at the peptides during the experimentation process. “While lysing the lenses we saw that there was a strong correlation with the protein aggregation and the presence of these peptides,” Dr. Sharma said. This becomes apparent when looking at the lens. “If you analyze a single lens, what you’ll see is that in the very center of the lens there is more protein aggregation,” Dr. Sharma said. “We saw the peptides accumulating in the same region.” After identifying these peptides, investigators placed them in a solution with proteins that began to aggregate. “That gave us a strong clue telling us that these peptides have a role in protein aggregation,” he said. This was a bit of a surprise to investigators since the role of the parent crystallins is to maintain the clarity of the lens by a process known as chaperoning. In a normal lens the peptides that break down from the crystallins are quickly shepherded from the eye with the help of other proteins. However, this is not so in an aged cataract lens where these peptides collect. “The peptide interferes in the alpha crystalline chaperone function,” Dr. Sharma said. Chaperoning activity in the eye declines as these peptides collect. As a result the lens starts to cloud and cataracts eventually develop. Investigators were a little taken aback to see this. “The parent protein is perfect,” Dr. Sharma said. “But the peptide coming out of the parent protein is toxic to the parent.”

There are still a lot of questions to answer before this new information can be put to clinical use. “Right now we don’t know how these peptides are generated and why they are accumulating,” Dr. Sharma said. Investigators need to clarify why these proteins are building up. “The lens is an unusual system; there is a very small amount of protein turnover,” Dr. Sharma said. “But we are puzzled as to why only this specific peptide accumulates.” Meanwhile the rest of the protein appears to continue to be routinely cleared away as it is in a healthy eye. Investigators hope to one day clinically target these toxic peptides. “The key will be to identify the causative factors for the formation of these peptides,” Dr. Sharma said. “Once we determine that, then we can specifically try to design compounds to stop that process.”

Wide-reaching applications

The application of the study goes far beyond the eye, Dr. Sharma believes. “There are other diseases where protein aggregation is involved,” he said. “One good example would be Alzheimer’s, which is a protein aggregation disease.” If investigators are able to find a way to keep the proteins from accumulating, this could be good news here as well. Another like condition might be prion disease. “If we design any compounds, or identify any compounds which can block the protein aggregation, that might be applicable to other protein aggregation diseases,” Dr. Sharma said. “A broader application is possible; the basic mechanism may be the same because they all have proteins and protein aggregation.”

Dr. Sharma also wonders whether age-related modifications resulting in the toxic peptides may show up in other areas of the body. “One can start looking at even other tissues in order to see if this is a phenomenon due to the aging process,” he said. “We could look in the brain, liver, or kidney to see if this is happening.”

Even for the eye alone, however, Dr. Sharma sees the new findings as important despite the fact that cataract surgery can usually easily remedy the problem. “People might feel that cataract surgery is a very successful surgery,” he said. “But the problem is before the cataract surgery, the patient has lost some of his or her quality of life.” While such patients can often still read, walk, and drive, they have diminished vision. “What we need to do is determine if we can suppress this protein aggregation light-scattering aging phenomenon,” Dr. Sharma said. “That way one need not worry about these things.”

Editors’ note: Dr. Sharma has no financial interests related to his comments.

Contact Information

Sharma: 573-882-8478,

Zeroing in on peptides’ role in cataract formation Zeroing in on peptides’ role in cataract formation
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