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Elucidating the microscopic nucleation mechanisms has opened new opportunities to develop therapeutics against toxic mechanisms and species. Here, we show that naturally occurring molecular chaperones, represented by the anti\u2010amyloid Bri2 BRICHOS domain, can be used to target \u03b1Syn\u2010associated nucleation processes and structural species related to neurotoxicity. Our findings revealed that BRICHOS predominantly suppresses the formation of new nucleation units on the fibrils surface (secondary nucleation), decreasing the oligomer generation rate. Further, BRICHOS directly binds to oligomeric \u03b1Syn species and effectively diminishes \u03b1Syn fibril\u2010related toxicity. Hence, our studies show that molecular chaperones can be utilized as tools to target molecular processes and structural species related to \u03b1Syn neurotoxicity and have the potential as protein\u2010based treatments against neurodegenerative disorders.<\/jats:p>","DOI":"10.1002\/pro.5091","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T09:31:27Z","timestamp":1720517487000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Specific inhibition of \u03b1\u2010synuclein oligomer generation and toxicity by the chaperone domain Bri2\n                    <scp>BRICHOS<\/scp>"],"prefix":"10.1002","volume":"33","author":[{"given":"Laur\u00e8ne","family":"Adam","sequence":"first","affiliation":[{"name":"Department of Biosciences and Nutrition Karolinska Institutet  Huddinge 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