The last decade of Parkinson's disease research heralded the discovery of specific genes mutated in rare familial disease cases. Investigating these rare gene mutations has provided a heightened understanding of pathogenic mechanisms linked to disease. A recent discovery of mutations in the the leucine-rich repeat kinase 2 (LRRK2) gene that results in autosomal-dominant PD provided another tool to develop new models to probe the mysteries of PD.
Examination of patients reveals that mutations in LRRK2 are a common cause of late-onset PD. In studying the biology of this protein and the disease causing mutations, we and others found that the mutations increased the enzymatic activity of LRRK2. We propose that drugs that block this increase in enzyme activity might be useful in the treatment of PD.
Our project proposes to use recent advances in chemical library screening and robotic high-throughput assay systems to systematically search for new drugs that can block the increase in LRRK2 activity. In future experiments successful drugs will be tested in experimental models of PD with the ultimate goal of taking an active drug to clinic.
Dr. Dawson established assays that could be used for chemical screening for LRRK2 kinase inhibitors. An initial screen identified compounds useful as research tools for examining LRRK2 function.