exploring The Far Reaches of I t was a parallel interest in pharmacology that led to a concern with Parkinson’s disease—a primary focus of Dr. Mouradian’s work since the mid-1980s, when she started at the National Institutes of Health (NIH) intramural program. “Among all the neurodegenerative diseases, Parkinson’s is the only one for which we have truly effective drugs to make a clear impact on symptoms,” she says. phate group from alpha-synuclein, and found it to protect the brain in two mouse models of Parkinson’s disease. What’s even more interesting is that the compound is present in coffee. “There is considerable epidemiological evidence that coffee consumption is associated with reduced risk of Parkinson’s disease,” says Dr. Mouradian. The next step is to find a suitable formulation to test in patients. Other work related to alpha-synuclein that is being pursued in the lab involves looking at the regulation of protein levels in the brain. “We know that an excess of alphasynuclein is bad for the brain,” says Dr. Mouradian. “If there are more than the normal two copies of the gene in the genome, let’s say an extra functional copy, the person STEVE HOCKSTEIN Her research encompasses a wide range of disciplines, from molecular and cell biologic studies to animal mod- els of Parkinson’s to clinical trials. “Of course, the Holy Grail in this field is to find ways to slow down the progression of disease—or stop it if possible,” says Dr. Mouradian. But the starting point is to understand the basis of the disease. In the past two decades, scientists have discovered a great deal about its genetic underpinnings. Dr. Mouradian’s laboratory carries out a number of studies at the bench to understand how those genetic underpinnings contribute to neurodegeneration. Then they are modeled into organisms or cells to see how that process unfolds from mutation to neurodegeneration. Using animal models, researchers study various interventions that can potentially have therapeutic applications in patients. Dr. Mouradian explains, “It’s a whole investigative process from a gene or a molecule—trying to understand what it does to the brain—and then using that information to understand the cascade of events that we can interdict at some point that’s therapeutically feasible.” develops Parkinson’s disease.” In collaboration with Eunsung Junn, PhD, assistant professor of neurology, the team launched an investigation to look at mechanisms that the brain uses to regulate alpha-synuclein level and found small RNA molecules called microRNAs—specifically, microRNA-7—that reduces the amount of this protein. This approach is another way in which toxicity of the alpha-synuclein protein can be modified. a Promise of new neuro-protective treatments Currently, Dr. Mouradian is leading a research effort on Parkinson’s disease surrounding the protein alpha-synuclein. The goal is to develop a neuro-protective or disease-modifying therapy for Parkinson’s. “This protein is abnormally aggregated in the brains of Parkinson’s patients and is excessively phosphorylated—which makes it more prone to aggregate and be toxic,” explains Dr. Mouradian. “We thought it would therefore make sense to try to minimize phosphorylation as one way to mitigate toxicity.” In collaboration with Jeffry Stock, PhD, professor of molecular biology at Princeton University, her lab has tested a compound that does just that, removing the phos42 Robert Wood Johnson I MEDICINE repurposing fda-approved Compound to target Parkinson’s symptoms Aside from neuro-protective approaches, Dr. Mouradian’s laboratory has been studying possibilities for better treatments of symptoms of Parkinson’s. A number of drugs are designed to treat the symptoms—most notably L-dopa—but they work well only initially. Over time, patients who take L-dopa develop a condition that manifests as involuntary movements—called L-dopa-induced dyskinesia, or LID— that forces some patients to undergo brain surgery. Based on work performed in Dr. Mouradian’s laboratory, a compound that the U.S. Food and Drug Admin-