Parkinson's Disease is a devastating neurological disorder for which there is no known cure. Our goal is to develop drug candidates to slow or halt the progression of PD. This will be done by focusing on very recent discoveries showing that mutations in a novel protein -- leucine-rich repeat kinase-2, or LRRK-2 -- are linked to a form of familial PD that closely resembles the sporadic disease. Mutations in this gene may account for as much as six percent of all familial PD cases and may underlie one to two percent of cases previously thought to be sporadic in nature, suggesting that this is a very important target for PD research. LRRK-2 is a large protein with multiple functional domains, including a protein kinase domain. Kinases regulate the function of other proteins transferring phosphate groups to them, and are typically involved in cell signaling pathways. Intriguingly, certain PD-associated mutations cause an increase in LRRK-2 kinase activity, suggesting that this activity may play a central role in pathogenesis. Kinase activity is often targeted for drug development, and Wyeth has well-recognized expertise in this approach, having multiple ongoing kinase inhibitor programs in several therapeutic areas. We will develop an assay of LRRK-2 kinase activity and use this to perform a high throughput screen of Wyeth's extensive compound library, followed by medicinal chemistry optimization to develop specific LRRK-2 kinase inhibitors. Furthermore, we will identify the native, biologically relevant substrates of LRRK-2 kinase activity in cells. Knowing the identity of these native substrates is very important to define signaling pathways that are perturbed in PD, and this may yield additional important targets for therapeutic intervention in this disease. With this knowledge, we will develop predictive models of the cellular abnormalities resulting from LRRK-2 activity to evaluate our drug candidates. To demonstrate efficacy, we will use state-of-the-art molecular techniques to transduce LRRK-2 expression in relevant brain regions of animals using viral vectors. At the completion of this work, we will have further defined the mechanistic role LRRK-2 plays in PD, and will have utilized the resources and expertise of Wyeth's large research-based pharmaceutical expertise to identify novel drug candidates for the treatment of PD.