{"doi":"10.1073/pnas.2217835120","title":"Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils","abstract":"The amyloid aggregation of alpha-synuclein within the brain is associated with the pathogenesis of Parkinson’s disease (PD) and other related synucleinopathies, including multiple system atrophy (MSA). Alpha-synuclein aggregates are a major therapeutic target for treatment of these diseases. We identify two small molecules capable of disassembling preformed alpha-synuclein fibrils. The compounds, termed CNS-11 and CNS-11g, disaggregate recombinant alpha-synuclein fibrils in vitro, prevent the intracellular seeded aggregation of alpha-synuclein fibrils, and mitigate alpha-synuclein fibril cytotoxicity in neuronal cells. Furthermore, we demonstrate that both compounds disassemble fibrils extracted from MSA patient brains and prevent their intracellular seeding. They also reduce in vivo alpha-synuclein aggregates in C. elegans . Both compounds also penetrate brain tissue in mice. A molecular dynamics–based computational model suggests the compounds may exert their disaggregating effects on the N terminus of the fibril core. These compounds appear to be promising therapeutic leads for targeting alpha-synuclein for the treatment of synucleinopathies.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":320527,"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":48,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":843505,"name":"Carolyn J. Hu","orcid":"0000-0001-6218-4034","position":1,"is_corresponding":false},{"id":244683,"name":"Hope Pan","orcid":"0000-0001-6509-6224","position":2,"is_corresponding":false},{"id":273522,"name":"Jiahui Lu","orcid":"0000-0002-4941-3098","position":3,"is_corresponding":false},{"id":473676,"name":"Romany Abskharon","orcid":"0000-0003-1350-0189","position":4,"is_corresponding":false},{"id":805248,"name":"Jeannette T. Bowler","orcid":"0000-0003-2428-3095","position":5,"is_corresponding":false},{"id":805251,"name":"Gregory M. Rosenberg","orcid":"0000-0002-1297-1715","position":6,"is_corresponding":false},{"id":298542,"name":"Christopher Kazu Williams","orcid":"0000-0003-3253-7630","position":7,"is_corresponding":false},{"id":1031230,"name":"Gazmend Elezi","orcid":"0000-0003-4087-3431","position":8,"is_corresponding":false},{"id":1031231,"name":"Melinda Balbirnie","orcid":"0000-0003-3497-392X","position":9,"is_corresponding":false},{"id":653177,"name":"Kym F. Faull","orcid":"0000-0001-9391-153X","position":10,"is_corresponding":false},{"id":244990,"name":"Harry V. Vinters","orcid":"0000-0002-2965-1240","position":11,"is_corresponding":false},{"id":473677,"name":"Paul M. Seidler","orcid":"0000-0001-8530-7244","position":12,"is_corresponding":false},{"id":225464,"name":"David Eisenberg","orcid":"0000-0003-2432-5419","position":13,"is_corresponding":false},{"id":298540,"name":"Kevin A. Murray","orcid":"0000-0003-1969-7701","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T01:07:22.377587Z","pmid":"36757890","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":[]}