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Brazilin Removes Toxic Alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium
J Mol Biol. 2021 Apr 16;433(8):166878. doi: 10.1016/j.jmb.2021.166878.
George R Nahass 1, Yuanzi Sun 2, Yong Xu 3, Mark Batchelor 2, Madeleine Reilly 2, Iryna Benilova 2, Niraja Kedia 4, Kevin Spehar 4, Frank Sobott 3, Richard B Sessions 5, Byron Caughey 6, Sheena E Radford 3, Parmjit S Jat 2, John Collinge 2, Jan Bieschke 7
Abstract:
...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.
PMID: 33610557
Free Full-Text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610480/