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 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 Lew...

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Bibliographic Details
Published in:Acta neuropathologica 2001-10, Vol.102 (4), p.329-334
Main Authors: SHARMA, Nutan, MCLEAN, Pamela J, KAWAMATA, Hibiki, IRIZARRY, Michael C, HYMAN, Bradley T
Format: Article
Language:English
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
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Summary: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.
ISSN:0001-6322
1432-0533
DOI:10.1007/s004010100369