Brazilin Removes Toxic Alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium.
Amyloid
Molecular Modelling
Neurdegeneration
Parkinson’s disease
Polyphenol
Journal
Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R
Informations de publication
Date de publication:
16 04 2021
16 04 2021
Historique:
received:
30
09
2020
revised:
06
01
2021
accepted:
05
02
2021
pubmed:
22
2
2021
medline:
23
6
2021
entrez:
21
2
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33610557
pii: S0022-2836(21)00072-3
doi: 10.1016/j.jmb.2021.166878
pmc: PMC7610480
mid: EMS119961
pii:
doi:
Substances chimiques
Amyloid
0
Amyloid beta-Peptides
0
Benzopyrans
0
alpha-Synuclein
0
brazilin
FZ39SW1K10
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
166878Subventions
Organisme : Wellcome Trust
ID : 208385
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/E012558/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1604/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 204963
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1004/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M02492X/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 204963/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_00024/6
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R21 NS101588
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00024/2
Pays : United Kingdom
Informations de copyright
Copyright © 2021. Published by Elsevier Ltd.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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