RT Journal Article SR Electronic T1 Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.09.29.318220 DO 10.1101/2020.09.29.318220 A1 George R. Nahass A1 Yuanzi Sun A1 Yong Xu A1 Mark Batchelor A1 Madeleine Reilly A1 Iryna Benilova A1 Niraja Kedia A1 Kevin Spehar A1 Frank Sobott A1 Richard B. Sessions A1 Byron Caughey A1 Sheena E. Radford A1 Parmjit Jat A1 John Collinge A1 Jan Bieschke YR 2020 UL http://biorxiv.org/content/early/2020/10/01/2020.09.29.318220.abstract AB 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, prompting our inquiry in its mechanism of action. 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 is distinct from other polyphenols and is also distinct from its effect on Aβ. Brazilin preserves the natively unfolded state of α-syn by stabilizing the compact conformation of the α-syn monomer over the aggregation-competent extended conformation. 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. Brazilin eliminates seeding competence of α-syn assemblies from Parkinson’s disease patient brain tissue, and treatment of pre-formed fibril assemblies with Brazilin significantly reduces their toxicity in primary neurons. Our findings suggest that Brazilin has substantial potential as a neuroprotective and therapeutic agent for Parkinson’s Disease.Highlights- The natural polyphenol Brazilin binds to monomeric, oligomeric and fibrillar α-syn- Brazilin shifts the equilibrium away from aggregation-competent monomer conformations- Brazilin inactivates seeding-competent α-syn isolated from Parkinson patients’ brains- Brazilin detoxifies α-syn aggregation intermediates and stabilizes mature amyloid fibrilsCompeting Interest StatementThe authors have declared no competing interest.