Nahass, GR, Sun, Y, Xu, Y et al. (12 more authors) (2021) Brazilin Removes Toxic Alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium. Journal of Molecular Biology, 433 (8). 166878. ISSN 0022-2836
Abstract
Alpha-synuclein (α-syn) fibrils, a major constituent of the neurotoxic Lewy Bodies in Parkinson’s disease, form via nucleation dependent polymerization and can replicate by a seeding mechanism. Brazilin, a small molecule derived from red cedarwood trees in Brazil, has been shown to inhibit the fibrillogenesis of amyloid-beta (Aβ) and α-syn as well as remodel mature fibrils and reduce cytotoxicity. Here we test the effects of Brazilin on both seeded and unseeded α-syn fibril formation and show that the natural polyphenol inhibits fibrillogenesis of α-syn by a unique mechanism that alters conformational equilibria in two separate points of the assembly mechanism: Brazilin preserves the natively unfolded state of α-syn by specifically binding to the compact conformation of the α-syn monomer. Brazilin also eliminates seeding competence of α-syn assemblies from Parkinson’s disease patient brain tissue, and reduces toxicity of pre-formed assemblies in primary neurons by inducing the formation of large fibril clusters. Molecular docking of Brazilin shows the molecule to interact both with unfolded α-syn monomers and with the cross-β sheet structure of α-syn fibrils. Our findings suggest that Brazilin has substantial potential as a neuroprotective and therapeutic agent for Parkinson’s disease.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 Published by Elsevier Ltd. This is an author produced version of an article published in Journal of Molecular Biology. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Amyloid; Parkinson’s disease; Neurdegeneration; Polyphenol; Molecular Modelling |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 208385/Z/17/Z |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 Mar 2021 14:11 |
Last Modified: | 19 Feb 2022 01:38 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.jmb.2021.166878 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:172514 |
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