Cholesterol-containing lipid nanodiscs promote an α-synuclein binding mode that accelerates oligomerization.

Autor: Jakubec M; Department of Biological Sciences, University of Bergen, Norway.; Department of Molecular Biology, University of Bergen, Norway., Bariås E; Department of Biological Sciences, University of Bergen, Norway.; Department of Molecular Biology, University of Bergen, Norway., Furse S; Department of Molecular Biology, University of Bergen, Norway., Govasli ML; Department of Biological Sciences, University of Bergen, Norway.; Department of Molecular Biology, University of Bergen, Norway.; Division of Infection and Immunity, University College London, London, UK., George V; Department of Chemistry, University of Bergen, Norway., Turcu D; Department of Biological Sciences, University of Bergen, Norway.; Department of Molecular Biology, University of Bergen, Norway., Iashchishyn IA; Department of Medical Biochemistry and Biophysics, Umeå University, Sweden., Morozova-Roche LA; Department of Medical Biochemistry and Biophysics, Umeå University, Sweden., Halskau Ø; Department of Biological Sciences, University of Bergen, Norway.; Department of Molecular Biology, University of Bergen, Norway.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2021 Mar; Vol. 288 (6), pp. 1887-1905. Date of Electronic Publication: 2020 Sep 26.
DOI: 10.1111/febs.15551
Abstrakt: Dysregulation of the biosynthesis of cholesterol and other lipids has been implicated in many neurological diseases, including Parkinson's disease. Misfolding of α-synuclein (α-Syn), the main actor in Parkinson's disease, is associated with changes in a lipid environment. However, the exact molecular mechanisms underlying cholesterol effect on α-Syn binding to lipids as well as α-Syn oligomerization and fibrillation remain elusive, as does the relative importance of cholesterol compared to other factors. We probed the interactions and fibrillation behaviour of α-Syn using styrene-maleic acid nanodiscs, containing zwitterionic and anionic lipid model systems with and without cholesterol. Surface plasmon resonance and thioflavin T fluorescence assays were employed to monitor α-Syn binding, as well as fibrillation in the absence and presence of membrane models. 1 H- 15 N-correlated NMR was used to monitor the fold of α-Syn in response to nanodisc binding, determining individual residue apparent affinities for the nanodisc-contained bilayers. The addition of cholesterol inhibited α-Syn interaction with lipid bilayers and, however, significantly promoted α-Syn fibrillation, with a more than a 20-fold reduction of lag times before fibrillation onset. When α-Syn bilayer interactions were analysed at an individual residue level by solution-state NMR, we observed two different effects of cholesterol. In nanodiscs made of DOPC, the addition of cholesterol modulated the NAC part of α-Syn, leading to stronger interaction of this region with the lipid bilayer. In contrast, in the nanodiscs comprising DOPC, DOPE and DOPG, the NAC part was mostly unaffected by the presence of cholesterol, while the binding of the N and the C termini was both inhibited.
(© 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
Databáze: MEDLINE
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