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Human beta-Synuclein Rendered Fibrillogenic by Designed Mutations
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posted on 2023-06-08, 06:10 authored by Shahin Zibaee, Graham Fraser, Ross Jakes, David Owen, Louise C Serpell, R Anthony Crowther, Michel GoedertFilamentous inclusions made of alpha-synuclein are found in nerve cells and glial cells in a number of human neurodegenerative diseases, including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. The assembly and spreading of these inclusions are likely to play an important role in the etiology of common dementias and movement disorders. Both alpha-synuclein and the homologous beta-synuclein are abundantly expressed in the central nervous system; however, beta-synuclein is not present in the pathological inclusions. Previously, we observed a poor correlation between filament formation and the presence of residues 73-83 of alpha-synuclein, which are absent in beta-synuclein. Instead, filament formation correlated with the mean beta-sheet propensity, charge, and hydrophilicity of the protein (global physicochemical properties) and beta-strand contiguity calculated by a simple algorithm of sliding averages (local physicochemical property). In the present study, we rendered beta-synuclein fibrillogenic via one set of point mutations engineered to enhance global properties and a second set engineered to enhance predominantly beta-strand contiguity. Our findings show that the intrinsic physicochemical properties of synucleins influence their fibrillogenic propensity via two distinct but overlapping modalities. The implications for filament formation and the pathogenesis of neurodegenerative diseases are discussed.
History
Publication status
- Published
Journal
Journal of Biological ChemistryISSN
0021-9258Publisher
American Society for Biochemistry and Molecular BiologyExternal DOI
Issue
49Volume
285Page range
38555-38567Pages
12.0Department affiliated with
- Biochemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06Usage metrics
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