Brazilin Removes Toxic Alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium.

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.

• Authors: George R Nahass, Yuanzi Sun, Yong Xu, Mark Batchelor, Madeleine Reilly, Iryna Benilova, Niraja Kedia, Kevin Spehar, Frank Sobott, Richard B Sessions, Byron Caughey, Sheena E Radford, Parmjit S Jat, John Collinge, Jan Bieschke
• Journal: Journal of molecular biology (J Mol Biol) Vol. 433 Issue 8 Pg. 166878 (04 16 2021) ISSN: 1089-8638 [Electronic] Netherlands
• PMID: 33610557 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Ltd.

Chemical References

• Amyloid
• Amyloid beta-Peptides
• Benzopyrans
• alpha-Synuclein
• brazilin

Topics

• Amyloid (metabolism)
• Amyloid beta-Peptides (metabolism)
• Animals
• Benzopyrans (chemistry, pharmacology)
• Brain (metabolism)
• Humans
• Mice
• Molecular Conformation
• Molecular Docking Simulation
• Neurons
• Parkinson Disease (metabolism)
• alpha-Synuclein (chemistry, metabolism, toxicity)