UAB researchers — who received a $200,000 grant from the Michael J. Fox Foundation to study a mutation gene, LRRK2 — have made a direct link between LRRK2 and the existence of Parkinson’s disease (PD) in some families. The grant allows researchers to study the role of kinase activity in the gene, but already the UAB Department of Neurology has determined the mutation gene’s relationship to heredity. Andrew West, PhD, is one of the lead researchers investigating the LRRK2 gene and its passage from generation to generation. It is breakthrough research, West said, particularly considering that 15 years ago PD was believed to have no ties to genetics. According to West, “The LRRK2 gene was identified in families that transmit Parkinson’s from one generation to the next in a dominant transmission. We analyzed (the family members’) DNA to find what was common among everyone who has the disease and those who don’t. In this case, (the ones with Parkinson’s) had the LRRK2 gene. We know that LRRK2 causes a percentage of Parkinson’s.” West said up to 5 percent of cases of Parkinson’s disease cases can be attributed to the LRRK2 mutation gene. Despite 95 percent of PD cases remaining with undetermined causes, the identification of the inherited LRRK2 gene is a positive step. “Nobody knows what causes the disease,” West said. “It is not linked with environmental factors, and Parkinson’s is not entirely genetic either. At this point, we’re not sure what causes the disease, which puts us in the same boat with other nerve disorders like Alzheimer’s and ALS. We won’t know what’s causing Parkinson’s until it is cured. The main reason is that we don’t have successful animal models that recapitulate Parkinson’s disease.” West said LRRK2 is part of a class of proteins considered modifiable by small molecules. That knowledge gives drug companies something to target — proteins with small molecules — and leads to a higher likelihood of finding some effective treatment. The LRRK2 gene may be the first viable lead for researchers to focus on. “We now have a specific, drugable target to go for, and pharmaceutical companies will be working on a program to target the gene,” West said of LRRK2, which was discovered in 2004. “We were the first to show what these variants were doing in people and increasing activity (of the small molecules) in test tubes.” Ultimately, the hope is that UAB studies targeting LRRK2 will lead to a treatment that could be administered early to patients, preventing the progression of the disease. According to West, UAB recently was awarded a grant by the Michael J. Fox Foundation to create an animal model. Once investigators’ findings are validated in animal studies, treatment can move forward to human research. “We’re moving forward as fast as we can to find animal models and molecules that do what we want to do,” West said. “Creating animal models is notoriously difficult, because we need to have the animals recapitulate in a much shorter time what happens to humans over decades.” Using mice as the chosen model, researchers will accelerate the disease pathology and still have it mimic what happens in humans. “Mice live for two years, and we have to squeeze everything we can into that time frame,” West said. “In many respects, the mouse is a good starting-out animal. We know the most about them and can manipulate them on the genetic level. And we have the tools to do that.” Though some Parkinson’s research has been conducted on invertebrates — fruit flies, worms and even yeast — West says his team believes the LRRK2 gene is relatively specific to mammals. “And it’s very important to model this in a mammalian system to be able to take it to the next level,” he said. A virus-based delivery system for gene therapy is a way of accelerating the pathology, causing a mouse to undergo the progression of the disease in two months compared to 15 years in a person. “We have to have a way to over-express our target,” West said. “We use a virus to deliver our genetic payload to the specific area of the brain. That produces a really robust phenotype.” In this case, LRRK2 will be used to deliver Parkinson’s to the mouse’s brain. “Think of this as a reverse gene therapy,” West said. “We’re not trying to develop a system in humans, but to create a disease model to test our small molecule therapies.” West has been involved in Parkinson’s research for close to 10 years — around the time the first gene was discovered that could be linked conclusively to Parkinson’s disease. “Research exploded with the gene discovery,” West said. “If you understand what a disease is doing, as in the case of LRRK2, you can understand the disease process.” West said that discovery 10 years ago led to installation of Udall Centers for Excellence and sparked a major initiative by the National Institutes of Health and the National Institute of Neurological Disorders and Stroke to research Parkinson’s. That interest has intensified in the scientific community, with UAB and a stellar research team at the hub. “Clinically, UAB has been the leader in Alabama for Parkinson’s research for a long time,” West said. “In terms of basic research in Parkinson’s disease, UAB has spearheaded the recruitment of a new chair, Ray Watts, from Emory University. He installed a director, David Standaert (professor of neurology and director of the UAB Center for Neurodegeneration and Experimental Therapeutics), who was involved in one of the Udall centers in Massachusetts General, Harvard. In the past few years, they have recruited leading researchers in the field who are in turn recruiting junior leaders, such as myself, to understand the (LRRK2) approach to Parkinson’s disease.” April 2008