HANOVER, NH - Seeking a cure for an inherited disease that causes blindness in over one million people worldwide, Dartmouth Medical School researchers have discovered a critical role for zinc in retinitis pigmentosa. The amount of zinc, a trace metal naturally absorbed by the body, can determine whether a key protein for vision functions normally or misfolds, they found.
An inability to successfully bind zinc to rhodopsin, a light receptor protein in the eye, can trigger retinitis pigmentosa (RP), a degenerative disease that leaves many patients legally blind by the age of 40. The findings parallel similar progress in harnessing essential trace metals in the body to treat several neurodegenerative diseases including Alzheimer's, Parkinson's and Lou Gehrig's Disease.
The research, appearing as the "Paper of the Week" in the August 20 issue of the Journal of Biological Chemistry (JBC), is the first confirmation that zinc is present and plays a significant role in the normal folding and functions of rhodopsin, and if defective, leads to retinal degeneration.
"We have found if there is not enough zinc in the body or there is a mutation in the zinc binding site, the protein rhodopsin will misfold and break down, triggering cell death, degeneration of the retina and eventually blindness," said John Hwa, MD, PhD, assistant professor of pharmacology and toxicology at Dartmouth Medical School. "What is especially exciting about this new direction in our research is that this characteristic of rhodopsin is very similar to other proteins implicated in many neurodegenerative and human diseases. The fact that a trace metal can have such a critical impact on rhodopsin's ability to function properly may point to significant advances for research in other devastating illnesses as well."
The principles of the protein rhodopsin may be extended to its relatives: G-protein coupled receptors that mediate numerous functions in the body including sight, taste, smell and many important hormonal responses in the body.
"Rhodopsin is a prototypical G-protein coupled receptor," said Aleksandar Stojanovic, a graduate student at DMS who co-authored the article with Hwa and Jeremiah Stitham at DMS. "The fact that it is so susceptible to misfolding and breakdown based on the level of zinc could open new frontiers of research for many diseases."
Hwa and colleagues discovered a cluster of RP mutations localized within and around the area where zinc is supposed to bind with rhodopsin. They investigated different amounts of zinc at the rhodopson binding site to determine what amount leads to a successful binding and what causes the protein to misfold. According to Hwa, zinc has a strong presence in the body; the average person has 2.3 grams of zinc, making it the second most prevalent trace metal behind iron.
"We are slowly figuring out the importance of everyday elements, like zinc, in maintaining normal function of proteins in the body," said Hwa. "In addition to rhodopsin, I predict that scientists will find that more and more proteins and receptors are impacted by trace metals and may open new areas in the treatment of neurodegenerative and other types of human diseases."
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