Crystallins and Cataracts

Crystallins are a collection of structural proteins found in the lens of the eye that help to focus light onto the retina. Over our lifetimes they can accumulate damage, losing their native structure and fusing together to form aggregates – ultimately leading to the development of cataracts. But how does this happen – and how can we prevent the process?

Eugene Serebryany (Department of Chemistry and Chemical Biology, Harvard University, USA) has been studying these proteins for a number of years. “We need a non-surgical treatment for cataracts for the millions of people who can never benefit from surgery, but first it is necessary to understand what goes wrong with eye lens crystallins to cause the disease,” he says.

Back in 2015, Serebryany discovered that wild-type (undamaged) crystallin promoted aggregation of the mutant version – without itself aggregating. “It had been known for some time that, in certain proteins, mutated molecules that fold into aberrant structures could template similar aberrant structures in the unmutated (wild-type) molecules of the same protein, leading to aggregation of both the mutant and the wild-type molecules,” he says. “Our hypothesis then was that a similar phenomenon could exist in eye lens crystallins – so it was very surprising to discover the reverse.”

His more recent research into the mechanism behind this phenomenon led him to another surprise (1). Using mass spectrometry, in vitro oxidation and mutational analysis, he and his Harvard-MIT team found that a process of oxidation-reduction was taking place between these crystallin protein molecules – disproving long-held theories that crystallins were inert.

“We have found that the crystallin proteins can pass disulfide bonds among themselves,” Serebryany says. “If they land on a damaged protein molecule, they get stuck with the disulfide bond, trapped in a sticky non-native structure, and forced to aggregate. In this way, the disulfides do no great harm to the structurally sound crystallin molecules, and may in fact be protective, but they drive the structurally weakened molecules into aggregates that scatter light.” 

Serebryany believes the findings take us a couple of steps towards understanding the mechanisms behind what is likely the most common type of cataract, though notes that there is probably a second aggregation-promoting mechanism at work – something he and his team are now studying. “The more we learn about the biochemistry and biophysics of cataract formation, the wider the space of therapeutic possibilities will be.”