The recent discovery of the first genes causing parkinsonism (familial Parkinson's disease (PD) and autosomal recessive juvenile parkinsonism) has made possible a new approach to PD based on study of the fundamental properties of the three gene products (alphaS, ubiquitin C-hydrolase (UCH), and Parkin). The investigators of this proposal come from an existing group of researchers within the Center for Neurologic Diseases (CND) at the Brigham and Women's Hospital and Harvard Medical School, with a long history of successful collaborative research in the area of Alzheimer's disease (AD) and prion diseases. Our research has focused on the gene products which cause familial forms of those diseases. Our groups are investigating aspects of the biology of the three PD gene products from biophysical properties to cellular function and protein metabolism, as well as the development and study of animal models. The projects in this program will cover the spectrum from basic structural properties of the alphaS to the capacity of alphaS to form the pathologic hallmark of PD, the Lewy body (Project l), to cellular models of as function (Project 2), to animal models involving as and parkin (Project 3). In addition, we intend to use combinatorial chemical and targeted genomics (Core B) methods to discover new chemical entities that target these proteins and new genes that may be involved. The insights obtained from all of these projects will be useful in elucidating the underlying etiology of PD but also in future drug discovery efforts. Preliminary Results suggest that an analogy exists between PD and AD in that each involve accelerated protein fibrillogenesis.