After showing that individuals who take levodopa, or l-dopa, for movement disorders such as Parkinson's disease are protected from developing macular degeneration, University of Arizona researcher Brian S. McKay is taking the next step in his quest to prevent the blinding eye disease, thanks to a $1.7 million grant from the National Eye Institute of the National Institutes of Health.
Macular degeneration, also known as age-related macular degeneration, or AMD, is a degenerative disease of the retina that causes loss of central vision. L-dopa is a naturally occurring molecule made in all pigmented tissues, including the retinal pigment epithelium, or RPE, of the eye, where it has a role in maintaining a healthy macula — the part of the eye's retina that provides the most high-acuity color vision.
McKay's discovery that the RPE expresses a receptor for l-dopa, and that this signaling pathway fosters the survival of the retina, led to a collaborative observational study that found that patients who take a synthesized form of l-dopa, a common treatment for Parkinson's, were far less likely to develop macular degeneration. And if they did develop the disease, the onset was delayed by nearly 10 years.
"We will follow up this critical observation with cell biological studies to determine how l-dopa's effect occurs," said McKay, associate professor of ophthalmology and vision science at the UA College of Medicine – Tucson. "This grant will help us determine whether we can repurpose l-dopa to halt the epidemic that age-related macular degeneration has become."
AMD is the most common cause of blindness in individuals older than 55 in developed countries, and more than 10 million people in the United States have AMD, according to the Foundation Fighting Blindness. AMD is particularly prevalent in the Southwest with its large retired population.
"The cause of AMD isn't known, so it's difficult to develop strategies to prevent it," McKay said. "There is no cure, and there are no treatments for early AMD, also known as 'dry' AMD. For the roughly 10 percent of AMD patients who develop 'wet' AMD, where abnormal blood vessels grow under the retina, there is an effective treatment. However, it requires repeated intraocular injections, which are expensive and associated with risks — and don’t stop the progression of the underlying disease."
McKay will test whether intersecting pathways related to dopamine signaling may be the actual driving force behind l-dopa's protective effect rather than l-dopa itself.
"This is a critical set of experiments because l-dopa is converted to dopamine in neurons and retinal pigment epithelial (RPE) cells," McKay said. "Both RPE cells and the retinal neurons have dopamine receptors. We identified a signaling molecule, GPR143, that controls two RPE activities likely to protect from AMD, and showed that l-dopa could drive both activities.
"The research will test whether GPR143 or other dopamine-related receptors bring about the protection from AMD in those taking l-dopa. Once the responsible receptors are identified, they can be targeted to develop new drugs or combination therapies to protect people from developing AMD."