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

• Published in: Acta neuropathologica Vol. 102; no. 4; pp. 329 - 334
• Main Authors: SHARMA, Nutan, MCLEAN, Pamela J, KAWAMATA, Hibiki, IRIZARRY, Michael C, HYMAN, Bradley T
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-10-2001; Springer Nature B.V
• Subjects: alpha-Synuclein; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Fluorescence resonance energy transfer; Hippocampus - pathology; Humans; Lewy bodies; Lewy Bodies - chemistry; Lewy Bodies - pathology; Medical sciences; Movement disorders; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Neurodegenerative diseases; Neurology; Neuropil; Neuropil - pathology; Parkinson Disease - pathology; Parkinson's disease; Protein Conformation; Spectrometry, Fluorescence; Substantia Nigra - pathology; Synuclein; Synucleins; Ubiquitin; Ubiquitin - metabolism; Ubiquitination; Human; Ubiquitin; Nervous system diseases; Pathogenesis; Lewy body disease; Parkinson disease; Resonance energy; Synuclein; Cerebral disorder; Genetic disease; Resonance fluorescence; Central nervous system disease; Degenerative disease; Extrapyramidal syndrome; Lewy body
• DOI: 10.1007/s004010100369
• EISSN: 1432-0533
• ISSN: 0001-6322

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.