Parkinson's disease (PD) affects 1 percent of the population over 60 years of age and is one of the most common motor disorders. A pathologic hallmark of PD is the deposition of intracellular protein inclusions known as Lewy bodies in the neurons of affected individuals. The protein alpha-synuclein is a primary component of Lewy bodies and recent evidence has implicated alpha-synuclein oligomerization as a key step in Lewy body formation and in PD neuropathology. The ultimate goal of this work will be the development of pharmaceuticals that can inhibit alpha-synuclein oligomerization and thus Lewy body formation and neurodegeneration. In this phase I grant we will identify and characterize peptide-based inhibitors of alpha-synuclein oligomerization. We will study the alpha-synuclein/alpha-synuclein and alpha-synuclein-peptide interactions and identify the structure/activity relationships involved in the peptide inhibition of alpha-synuclein oligomerization. Finally, we will verify the plausibility of using a-synuclein oligomerization inhibitors in a cell culture model of Lewy body formation. This work will lay the foundation for a phase H grant in which we will identify small molecule drug candidates that act as a-synuclein oligomerization inhibitors, and begin pre-clinical testing of both the small molecule and peptide-based drug candidates in animal models of Lewy body disease.