Structural and mechanistic insights into amyloid-β and α-synuclein fibril formation and polyphenol inhibitor efficacy in phospholipid bilayers
Date
2022
Authors
Sanders, H.M.
Jovcevski, B.
Marty, M.T.
Pukala, T.L.
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Advisors
Journal Title
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Type:
Journal article
Citation
The FEBS Journal, 2022; 289(1):215-230
Statement of Responsibility
Henry M. Sanders, Blagojce Jovcevski, Michael T. Marty and Tara L. Pukala
Conference Name
Abstract
Under certain cellular conditions functional proteins undergo misfolding, leading to a transition into oligomers which precede formation of amyloid fibrils. Misfolding proteins are associated with neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. While the importance of lipid membranes in misfolding and disease aetiology is broadly accepted, the influence of lipid membranes during therapeutic design has been largely overlooked. This study utilized a biophysical approach to provide mechanistic insights into the effects of two lipid membrane systems (anionic and zwitterionic) on the inhibition of amyloid-β 40 and α-synuclein amyloid formation at the monomer, oligomer and fibril level. Large unilamellar vesicles (LUVs) were shown to increase fibrillization and largely decrease the effectiveness of two well-known polyphenol fibril inhibitors, (-)-epigallocatechin gallate (EGCG) and resveratrol, however, use of immunoblotting and ion-mobility mass spectrometry revealed this occurs through varying mechanisms. Oligomeric populations in particular were differentially affected by LUVs in the presence of resveratrol, an elongation phase inhibitor, compared to EGCG, a nucleation targeted inhibitor. Ion-mobility mass spectrometry showed EGCG interacts with or induces more compact forms of monomeric protein typical of off-pathway structures, however binding is reduced in the presence of LUVs, likely due to partitioning in the membrane environment. Competing effects of the lipids and inhibitor, along with reduced inhibitor binding in the presence of LUVs, provides a mechanistic understanding for decreased inhibitor efficacy in a lipid environment. Together, this study highlights that amyloid inhibitor design may be misguided if effects of lipid membrane composition and architecture are not considered during development.
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Dissertation Note
Provenance
Description
First published: 16 July 2021
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© 2021 Federation of European Biochemical Societies.