Human beta-synuclein rendered fibrillogenic by designed mutations.
Filamentous inclusions made of α-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 α-synuclein and the homologous β-synuclein are abundantly expressed in the central nervous system; however, β-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 α-synuclein, which are absent in β-synuclein. Instead, filament formation correlated with the mean β-sheet propensity, charge, and hydrophilicity of the protein (global physicochemical properties) and β-strand contiguity calculated by a simple algorithm of sliding averages (local physicochemical property). In the present study, we rendered β-synuclein fibrillogenic via one set of point mutations engineered to enhance global properties and a second set engineered to enhance predominantly β-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.
Zibaee
Shahin
S
Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
Fraser
Graham
G
Jakes
Ross
R
Owen
David
D
Serpell
Louise C
LC
Crowther
R Anthony
RA
Goedert
Michel
M
D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051846:beta-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D046912:Multiprotein Complexes; D051844:alpha-Synuclein; D051846:beta-Synuclein