Nurr1 has been discovered as one of the key factors regulating survival and maintenance of midbrain dopamine neurons. Last year, Le and collaborators (Nature Genetics, 3:385, 2003) reported the intriguing finding of point mutations in the Nurr1 gene associated with the development of familiar Parkinson's disease, suggesting that impaired Nurr1 function may be associated with impaired function and increased vulnerability of those midbrain dopamine neurons that degenerate in Parkinson's disease. The goal of this project is, first, to model, in rodents, the type of Nur1 dysfunction seen in the familial cases, and secondly, to use this new model to clarify the role of Nurr1 in the pathogenesis of Parkinson's disease. The experiments are designed to provide critical preclinical experimental data that may serve as a basis for novel strategies for disease intervention using Nurr1 gene delivery, or the development of novel pharmaco-therapies based on Nurr1 as a drug target.