Alpha-synuclein has an altered conformation and shows a tight intermolecular interaction with ubiquitin in Lewy bodies

alpha -Synuclein, a protein in which two mutations have been identified tha t cause autosomal dominant Parkinson's disease, is thought to serve as a ni dus for the development of a Lewy body. We hypothesized that alpha -synucle in would display different intra- and intermolecular associations in Lewy b odies than it does in its normal intracellular compartments. Using sensitiv e fluorescence resonance energy transfer (FRET) techniques, we found eviden ce that alpha -synuclein is more compact and in closer association with oth er alpha -synuclein molecules in Lewy bodies than it is in the neuropil. In addition, we found evidence of a close, direct intermolecular interaction between the N terminus of alpha -synuclein and ubiquitin. These observation s provide support for the hypothesis that in Lewy bodies alpha -synuclein a dopts an altered three-dimensional structure and undergoes N-terminal ubiqu itination.