title: Alpha-synuclein has an altered conformation and shows a tight intermolecular interaction with ubiquitin in Lewy bodies.
abstract: Alpha-synuclein, a protein in which two mutations have been identified that cause autosomal dominant Parkinson's disease, is thought to serve as a nidus for the development of a Lewy body. We hypothesized that alpha-synuclein would display different intra- and intermolecular associations in Lewy bodies than it does in its normal intracellular compartments. Using sensitive fluorescence resonance energy transfer (FRET) techniques, we found evidence that alpha-synuclein is more compact and in closer association with other 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 observations provide support for the hypothesis that in Lewy bodies alpha-synuclein adopts an altered three-dimensional structure and undergoes N-terminal ubiquitination.
authors.affiliation: Department of Neurology, Massachusetts General Hospital East, Charlestown 02129, USA.
authors.forename: N
authors.initials: N
authors.lastname: Sharma
authors.forename: P J
authors.initials: PJ
authors.lastname: McLean
authors.forename: H
authors.initials: H
authors.lastname: Kawamata
authors.forename: M C
authors.initials: MC
authors.lastname: Irizarry
authors.forename: B T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D006624:Hippocampus / Q000473:pathology; D006801:Humans; D016631:Lewy Bodies / Q000737:chemistry / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D019581:Neuropil / Q000473:pathology; D010300:Parkinson Disease / Q000473:pathology*; D011487:Protein Conformation; D013050:Spectrometry, Fluorescence; D013378:Substantia Nigra / Q000473:pathology; D051843:Synucleins; D025801:Ubiquitin / Q000378:metabolism*; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D025801:Ubiquitin; D051844:alpha-Synuclein