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In this study, we compare the phase behavior of four \u03b1Syn isoforms (\u03b1Syn-140, \u03b1Syn-126, \u03b1Syn-112, and \u03b1Syn-98). Using different biophysical tools including confocal microscopy, kinetic assays and microfluidic-based approaches, we find stark differences between the four systems in their propensities to undergo phase separation and aggregation. Furthermore, we show that even small amounts of \u03b1Syn-112, one of the predominant isoforms after \u03b1Syn-140, can affect the phase separation of \u03b1Syn-140. These results highlight the importance of conducting further investigations to elucidate the role of alternative splicing in synucleinopathies.<\/jats:p>","DOI":"10.1126\/sciadv.adq5396","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T13:58:56Z","timestamp":1744811936000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":25,"title":["Aggregation of \u03b1-synuclein splice isoforms through a phase separation pathway"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0500-4815","authenticated-orcid":true,"given":"Alexander","family":"R\u00f6ntgen","sequence":"first","affiliation":[{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1964-8432","authenticated-orcid":true,"given":"Zenon","family":"Toprakcioglu","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4816-9852","authenticated-orcid":true,"given":"Samuel T.","family":"Dada","sequence":"additional","affiliation":[{"name":"Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK."}],"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, Cambridge CB2 1EW, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7879-0140","authenticated-orcid":true,"given":"Tuomas P. 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