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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,7,22]]},"abstract":"<jats:p>The aggregation of amyloid-\u03b2 (A\u03b2) and \u03b1-synuclein (\u03b1Syn) into insoluble proteinaceous deposits is a hallmark of Alzheimer\u2019s and Parkinson\u2019s diseases. Recent evidence suggests that these amyloidogenic proteins act in synergy, with their coaggregation frequently observed in these disorders. In this study, we investigate the interaction of A\u03b2 and \u03b1Syn using various biophysical tools. In particular, we explore the cocondensation of A\u03b2 with \u03b1Syn, elucidating the pathways through which A\u03b2 modulates \u03b1Syn phase separation. We studied different variants of A\u03b2, focusing on the most prominent species, namely A\u03b242 and A\u03b240. We found that A\u03b242 and A\u03b240 have fundamentally different mechanistic effects on the kinetics of \u03b1Syn condensation. A\u03b242 initially forms large aggregates that act as heterogeneous nucleation sites which initiate the phase separation of \u03b1Syn. In contrast, A\u03b240 is sequestered into \u03b1Syn condensates where it accelerates the liquid-to-solid transition of \u03b1Syn into amyloid aggregates. All other A\u03b2 variants we probed fell into one of these two mechanistic pathways, with A\u03b237, A\u03b239, and A\u03b235-25 exhibiting similar behavior to A\u03b240, whereas A\u03b243 triggered nucleation processes similar to A\u03b242. Given the complexity behind amyloid formation, it is key to understand how molecular partners can interact with one another. Our results thus illustrate the extreme sensitivity of protein mixtures and shed light on some of the mechanisms involved in the cocondensation and aggregation of A\u03b2 with \u03b1Syn.<\/jats:p>","DOI":"10.1073\/pnas.2501987122","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T19:01:31Z","timestamp":1752519691000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":20,"title":["Amyloid-\u03b2 modulates the phase separation and aggregation of \u03b1-synuclein"],"prefix":"10.1073","volume":"122","author":[{"given":"Alexander","family":"R\u00f6ntgen","sequence":"first","affiliation":[{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zenon","family":"Toprakcioglu","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Owen M.","family":"Morris","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3616-1610","authenticated-orcid":false,"given":"Michele","family":"Vendruscolo","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge","place":["Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,7,14]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606210"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.13"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01249-0"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3810"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0238-6"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/42166"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.23.11282"},{"key":"e_1_3_4_8_2","first-page":"367","article-title":"Abnormal accumulation of NACP\/alpha-synuclein in neurodegenerative disorders","volume":"152","author":"Takeda A.","year":"1998","unstructured":"A. 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