The study, appearing in the October 3 issue of the Journal of Biological Chemistry, highlights research conducted on the gene rhodopsin, a protein located in the back of the eye that is credited with helping sight in dim or low-light conditions. It is one of several proteins in the retina that controls how light is detected. The mutation linked to RP can be traced to the photoreceptor, rhodopsin. A single mutation, state the researchers, can cause a cascade of retinal events that leads to retinitis pigmentosa and eventual blindness.
"We wanted to concentrate on the reasons why rhodopsin is prone to misfold; that way we have the best chance of correcting that distortion before the disease can worsen," said lead author, John Hwa, MD, PhD, an assistant professor of pharmacology and toxicology at Dartmouth Medical School.
Retinitis pigmentosa is a degenerative disease that affects the photoreceptors in the retina. It begins with a single mutation within the rhodopsin protein that triggers a domino effect and, over a period of years, the mutation is responsible for aggregation of the protein, death of the individual retinal cells, destruction of the retina and eventually blindness.
"Basically, if we can stabilize the second domino after the first has fallen, we will be on our way for a cure to this disease that makes 1 million people go blind around the world," said Hwa. "We needed to understand the problem at the level of the protein then we can design a ligand or drug to stabilize the abnormal protein to make sure it is destroyed properly." Hwa and colleagues used two techniques to pinpoint the mutations, which enabled them to decipher which of rhodopsin's 348 amino acids were distorted.
The first technique used, compensatory mutations, is a method of inserting different amino acids into a protein to instigate change and tracking where the repercussions occur. Researchers then mapped those changes using crystal structure-based molecular modeling to locate the specific areas on the rhodopsin protein where the mutations took place. Once the location of the mutations was known, the researchers introduced new amino acids to attempt to stabilize the protein before any further damage could occur.
"We now have a molecular understanding of the abnormal proteins," said Hwa, "so we can move ahead to the ultimate goal of designing effective drugs to delay the degeneration that occurs to people suffering from RP." He and co-authors Aleksander Stojanovic and Irene Hwang from Dartmouth Medical School plan to push ahead with their research, concentrating on the impact of certain Vitamin A derivatives on the rhodopsin mutations.
CONTACT: DMS Communications
September 30, 2003
603-650-1492
Journal
Journal of Biological Chemistry