By Alexandra Scammell
By determining how proteins in different areas of the eye’s lens change over time, researchers from Vanderbilt University’s School of Medicine Basic Sciences have learned more about how they could contribute to the mysterious progression of cataracts—a clouding of the lens that affects more than 65 million people worldwide each year.
“The risk of cataract onset increases as we age, so we want to know what causes that cataract to occur,” said Lee Cantrell, doctoral candidate in the Chemical and Physical Biology Program and lead author of the study, which was published in Molecular & Cellular Proteomics. He performed the work with Kevin Schey, professor of biochemistry, ophthalmology and visual sciences, and Romell Gletten, a recent graduate of the Department of Biochemistry.
Cantrell likens the lens to a tree trunk: The center of the lens has fiber cells that were formed in utero and are as old as we are. But moving outward, progressively younger and younger fiber cells are found. With this concept in mind, the researchers obtained 16 healthy lenses and focused on three regions that correspond to relative developmental stages. “We’re not looking at cataract formation necessarily, but we’re looking at … how the lens changes as it relates to age,” Cantrell said. “We’re not just looking at tissue aging, we’re looking at protein aging and what might happen within each region of the lens … over a lifetime.”
The researchers built on previous work that harnessed mass spectrometry, an analytical technique that measures the mass-to-charge ratio of molecules and is the conventional tool for doing proteomics—the study of proteins. Mass spectrometry measures more than one protein at a time and is quantitatively robust. They also employed an unconventional approach—data-independent acquisition—that allowed them to better identify scarce and difficult-to-measure molecular structures in the lens.
Because proteins degrade with age and become harder and harder to measure, using DIA is “significantly more capable of measuring these low-abundance peptides and proteins,” Cantrell said. “That’s what we’re doing here—we’re enhancing our capabilities with these next-generation techniques,” he said.
What Cantrell and the team found is that, generally, large changes in protein abundances occur once a person reaches age 50. “There’s an approximate cutoff between younger-than-50 and older-than-50 lenses, where there’s a transition in the compositional abundance of all proteins,” Cantrell said. For example, the team found that the protein SLC24A2—a calcium transporter—significantly modified with age.
Although this research contributes to the understanding of lens changes with age and cataract formation, it is not yet known if these identified proteins are functional. According to Cantrell, there’s still the question of causality and correlation—this research does not answer that, he said.
There’s “a long way to go” until scientists can complete ideal in vitro (in a tube or dish) and in vivo (in living organisms) studies looking for therapeutics to target human cataract formation, Cantrell said, but “it’s certainly in the long-term horizon.”
In the nearer future, this work lays a foundation for research into the functional significance of individual proteins, including low-abundance proteins like SLC24A2. Researchers can take a target like SLC24A2 and perturb a system to evaluate its function. This research is “opening up new chapters and entirely new research projects,” Cantrell said.