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

By 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 Jat, John Collinge, Jan Bieschke

Posted 01 Oct 2020
bioRxiv DOI: 10.1101/2020.09.29.318220

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 ![Figure][1]</img> ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes

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