Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.29.318220v1?rss=1 Authors: Nahass, G. R., Sun, Y., Xu, Y., Batchelor, M., Reilly, M., Benilova, I., Kedia, N., Spehar, K., Sobott, F., Sessions, R. B., Caughey, B., Radford, S. E., Jat, P., Collinge, J., Bieschke, J. Abstract: Alpha-synuclein (-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 (A{beta}) and -syn, prompting our inquiry in its mechanism of action. Here we test the effects of Brazilin on both seeded and unseeded -syn fibril formation and show that the natural polyphenol inhibits fibrillogenesis of -syn by a unique mechanism that is distinct from other polyphenols and is also distinct from its effect on A{beta}. Brazilin preserves the natively unfolded state of -syn by stabilizing the compact conformation of the -syn monomer over the aggregation-competent extended conformation. Molecular docking of Brazilin shows the molecule to interact both with unfolded -syn monomers and with the cross-{beta} sheet structure of -syn fibrils. Brazilin eliminates seeding competence of -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. Copy rights belong to original authors. Visit the link for more info