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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,2,14]]},"abstract":"<jats:p>\n                    The amyloid aggregation of alpha-synuclein within the brain is associated with the pathogenesis of Parkinson\u2019s 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\u00a0vitro, 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\u00a0vivo alpha-synuclein aggregates in\n                    <jats:italic>C. elegans<\/jats:italic>\n                    . Both compounds also penetrate brain tissue in mice. A molecular dynamics\u2013based 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2217835120","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T12:58:12Z","timestamp":1675947492000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":52,"title":["Small molecules disaggregate alpha-synuclein and prevent seeding from patient brain-derived fibrils"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1969-7701","authenticated-orcid":false,"given":"Kevin A.","family":"Murray","sequence":"first","affiliation":[{"name":"Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, Molecular Biology Institute, UCLA, Los Angeles, CA 90095"},{"name":"HHMI, UCLA, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn 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