Issue date: 6/14/07 Section: News

Media Credit: Spencer Selvidge There are approximately 10,000 zebra fish kept in a few hundred tanks hidden away in assistant professor Brian Perkins's lab in Biological Sciences Building East. The adult fish, growing to around 3.8 cm, are kept as a breeding population for nine different recessive genetic traits. [Click to enlarge]

Media Credit: Spencer Selvidge Professor Brian Perkins is interested in understanding the genes required for photoreceptor development and maintenance. [Click to enlarge]

Media Credit: Spencer Selvidge Shown above are a normal (top) and mutant (bottom) zebra fish. The mutant does not have as many rod photoreceptors and has smaller eyes, but the rest of the fish is normal. [Click to enlarge]

Researchers at Texas A&M have identified key components behind a rare form of blindness in humans, and have brought the scientific community one step closer to treating, even preventing, what once seemed like an incurable disease.

A&M biologist Brian Perkins has worked on the study of protein transport within photoreceptors - the rod and cone cells that detect light and allow organisms to view the world - since he began his post-doctoral training at Harvard University in 2000. Perkins arrived at A&M in 2004 and continued his study of protein transport, which is his main area of research.

"My research involves looking at the genetic bases for various forms of human blindness, mainly the development of the retina and retinal degenerations, because a lot of the genes are the same ones that are required to maintain the retina throughout the life of the eye," Perkins said. "If you can understand how the retina develops, then you can gain insight into how they are maintained."

Perkins said he was led to this particular study of photoreceptor degeneration in zebra fish through his interest in the process of protein transport and the specific mutated gene that causes the rare but aggressive human disease choroideremia - an X-linked retinal degenerative disease that leads to blindness in an estimated one in every 100,000 people. Severe loss of vision starts at an early age, with some people experiencing complete blindness by their mid-30s to early 40s.

"I wasn't interested specifically in this particular disease, but instead the protein. Rab escort protein-1 (REP1), which is a protein that helps regulate intracellular traffic in photoreceptors as well as the retinal pigment epithelium (RPE) tissue," Perkins said. "We had a suspicion that REP1 would be involved in the process of retinal degeneration, but the fact that it also corresponds to a human disease gene makes it even more interesting - the icing on the cake - because it will obviously have direct ramifications on future work concerning this disease."

Choroideremia is a recessive disease, and those affected by it are missing the good form of REP1, Perkins said. The number of photoreceptors, like the number of cells in the brain, are fixed and do not regenerate when defective. Perkins said by the time people realize they have this particular disease, their vision is failing and they have lost a fair number of rods and cones.

For the study, Perkins used a line of mutant zebra fish developed by Dr. Jim Hudspeth from Rockefeller University. "The Hudspeth lab isolated the line of zebra fish and mutated them. Once they cloned the gene, we knew it would likely be involved in vision and choroideremia just by reading the literature," Perkins said. "We requested some of the fish and off we went."

Working in collaboration with Dr. Joseph Bilotta from the University of Western Kentucky and A&M biology graduate student Bryan Krock, Perkins hypothesized photoreceptor death was a secondary consequence due to problems in the RPE instead of the more common assertion that photoreceptors died because of an intrinsic defect. Before this research, there was some debate within the literature whether or not the cell death was photoreceptor specific or secondary due to RPE, Perkins said.

"There are two ways for the photoreceptors to die: if the gene is missing then an intrinsic death could occur because of a lack of the REP1 protein in the photoreceptors; alternatively, if the RPE cells need the gene, due to their role in supporting photoreceptors and lack it, then that can cause a second degeneration of the photoreceptors," Perkins said. "The question that we were really asking was: why do these photoreceptors die?"

To test their hypothesis they transplanted cells from a mutated zebra fish into a normal, healthy fish and then looked to see how the cells reacted. The transplanted cells were either mutated photoreceptor cells or mutated RPE cells.

Perkins said they used zebra fish in their study because the zebra fish eye is very similar to the human eye, both in physiology, anatomy and function.

"The zebra fish retina can be a very good model for the human retina, in some cases people argue it is an even better model than a mouse eye," Perkins said. "In addition, the fish are cheap to maintain, great for genetic studies and we can detect mutations within five days of development in a fish, whereas it might take 10 years to occur in humans."

After testing, the group found that a defect in the RPE was sufficient to cause the photoreceptors to die even if the photoreceptors were normal. "We found the mutated genes seem to function in the RPE," Perkins said. "What that says is that the RPE is required for the photoreceptor survival."

Perkins said with these findings there is potential for a correction or prevention of this disease in the early stages. Perkins emphasized that a mutated RPE is sufficient to induce degeneration of the photoreceptor early, but they don't know its long-term fate.

"Scientists were never sure which tissues were affected by this disease; by understanding the RPE tissue is the one affected we predict more specific therapies can be developed," Perkins said. "Once you restore the good copy of the gene, REP1, to the RPE tissue, then presumably you would restore the function and the photoreceptors would survive."

Krock, who received his undergraduate degree from Penn State, helped with many of the experiments and was pleased with the results. "We were able to utilize our model system and find out very important things about how certain diseases manifest themselves, what happens, how it happens and how to treat it."

The findings were published in the Proceedings of the National Academy of Sciences.

Richard Ewing, the vice president for research, said Perkins' research is significant because it is using a unique research specimen to help understand a rare and incurable human disease. "A&M is very proud of its world renown researchers, like Dr. Perkins, and their contributions to society. Their work is a fundamental part of our mission."

Ewing said A&M has research initiatives totaling almost $500 million annually, mostly funded from outside sources.

Page 1 of 1

Article Tools