{"doi":"10.1101/2020.09.29.318220","title":"Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium","abstract":"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, 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 fibrils Graphical Abstract","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":127421,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":576714,"name":"Yuanzi Sun","orcid":null,"position":1,"is_corresponding":false},{"id":576184,"name":"Yong Xu","orcid":"0000-0002-8389-4120","position":2,"is_corresponding":false},{"id":576185,"name":"Mark Batchelor","orcid":"0000-0001-6847-5131","position":3,"is_corresponding":false},{"id":576186,"name":"M. Reilly","orcid":"0000-0001-7666-0257","position":4,"is_corresponding":false},{"id":576187,"name":"Iryna Benilova","orcid":"0000-0001-7159-5820","position":5,"is_corresponding":false},{"id":576715,"name":"Niraja Kedia","orcid":null,"position":6,"is_corresponding":false},{"id":464074,"name":"Kevin Spehar","orcid":"0000-0003-2099-4914","position":7,"is_corresponding":false},{"id":267558,"name":"Frank Sobott","orcid":"0000-0001-9029-1865","position":8,"is_corresponding":false},{"id":483209,"name":"Richard B. Sessions","orcid":"0000-0003-0320-0895","position":9,"is_corresponding":false},{"id":227561,"name":"Byron Caughey","orcid":"0000-0002-3928-6101","position":10,"is_corresponding":false},{"id":298796,"name":"Sheena E. Radford","orcid":"0000-0002-3079-8039","position":11,"is_corresponding":false},{"id":300779,"name":"Parmjit Jat","orcid":"0000-0002-3354-0594","position":12,"is_corresponding":false},{"id":300803,"name":"John Collinge","orcid":"0000-0003-2220-7566","position":13,"is_corresponding":false},{"id":576188,"name":"Jan Bieschke","orcid":"0000-0002-3485-9767","position":14,"is_corresponding":false},{"id":576183,"name":"George R. Nahass","orcid":"0000-0001-9395-0862","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":null,"created_at":"2026-07-18T23:15:30.930746Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}