Researchers use model organism to test new therapies for retinal degeneration

Research by Johns Hopkins sensory biologists studying fruit flies, has revealed a critical step in fly vision. Humans with problems in this same step suffer retinal dystrophies, which manifest as visual defects ranging from mild visual impairments to complete blindness. The article, published Jan. 26 in Current Biology paves the way for using the fruit fly to screen for therapies to treat human retinal degeneration.

Retinal dystrophies result from inherited defects in nearly every step of the so-called "visual cycle," a series of biochemical reactions known to occur in vertebrates, which recycles the molecule that enables light detection in eye cells. "Therapeutic approaches to tackle such retinal dystrophies are very limited," says Craig Montell, Ph.D., a professor of biological chemistry and of neuroscience at the Johns Hopkins University School of Medicine. "So it's useful to take advantage of simpler experimental model organisms, like fruit flies, to tease apart complex systems like vision, then translate that to use in vertebrates."

This visual cycle previously was not thought to exist in invertebrate eyes. In fact, according to Montell, those who study fly vision long thought that as the molecules in the fly eye responsible for capturing photons of light can be regenerated by absorbing more light, they don't need a visual cycle for the cells to reuse the molecule.

Curious about whether one particular enzyme in the fly eye - pigment-cell-enriched dehydrogenase (PDH) - plays a role in the fly's ability to make the molecules that sense light, Montell and his research team generated flies carrying a mutation in the gene encoding PDH. They found the newly hatched flies lacking PDH to be totally normal in their ability to respond to light.

"It was a surprise. Initially the PDH looked dispensable as the visual responses were normal, but over time the pigment degraded," says Montell. "This led us to ask the question: If PDH doesn't make new light-sensing molecules, and flies can recycle them using light anyway, why are these flies losing their light-detecting molecules and consequently their sight?"

As it turns out, Montell and his team found PDH is required to help recycle the used light-capturing molecules in a previously unrecognized visual cycle in flies. Flies can recycle the molecules by absorbing light, but eventually the protein that holds the molecules in the cells needs to be replaced with new protein. When this happens the biochemical visual cycle is needed to regenerate the light sensing molecules. Over time, in pdh mutant flies, without a functional visual cycle, the used light-sensitive molecules were not regenerated causing cells in the retina to die, leading to vision loss.

To get an idea of how comparable the visual cycle is in flies and mammals, the team replaced the fly gene for PDH with a gene for a similar mammalian enzyme. These flies had normal electrical activity in cells of the retina in response to light, were able to maintain proper levels of light sensitive molecules, and had healthy retinas. This experiment showed the researchers that there are similarities in the visual cycles in mammals and flies.

"Flies are a good model in which to study and test new therapies for retinal degeneration," says Montell. "This research opens the door to using flies as a way to look for drugs to reduce human retinal degeneration due to defects in the visual cycle."