Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 49, Pages 38555-38567Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.160721
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Funding
- Alzheimer's Research Trust
- Multiple System Atrophy Trust
- Alzheimers Research UK [ART-PG2004A-5, ART-PG2007-3] Funding Source: researchfish
- Medical Research Council [MC_U105178803, MC_U105184319, MC_U105184291] Funding Source: researchfish
- MRC [MC_U105184291, MC_U105178803, MC_U105184319] Funding Source: UKRI
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Filamentous 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.
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