{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:10:35Z","timestamp":1791198635651,"version":"4.1.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"44","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,11,2]]},"abstract":"<jats:p>Because oligomers and aggregates of the protein \u03b1-synuclein (\u03b1S) are implicated in the initiation and progression of Parkinson\u2019s disease, investigation of various \u03b1S aggregation pathways and intermediates aims to clarify the etiology of this common neurodegenerative disorder. Here, we report the formation of short, flexible, \u03b2-sheet-rich fibrillar species by incubation of \u03b1S in the presence of intermediate (10\u201320% v\/v) concentrations of 2,2,2-trifluoroethanol (TFE). We find that efficient production of these TFE fibrils is strongly correlated with the TFE-induced formation of a monomeric, partly helical intermediate conformation of \u03b1S, which exists in equilibrium with the natively disordered state at low [TFE] and with a highly \u03b1-helical conformation at high [TFE]. This partially helical intermediate is on-pathway to the TFE-induced formation of both the highly helical monomeric conformation and the fibrillar species. TFE-induced conformational changes in the monomer protein are similar for wild-type \u03b1S and the C-terminal truncation mutant \u03b1S1-102, indicating that TFE-induced structural transitions involve the N terminus of the protein. Moreover, the secondary structural transitions of three Parkinson\u2019s disease-associated mutants, A30P, A53T, and E46K, are nearly identical to wild-type \u03b1S, but oligomerization rates differ substantially among the mutants. Our results add to a growing body of evidence indicating the involvement of helical intermediates in protein aggregation processes. Given that \u03b1S is known to populate both highly and partially helical states upon association with membranes, these TFE-induced conformations imply relevant pathways for membrane-induced \u03b1S aggregation both in vitro and in vivo.<\/jats:p>","DOI":"10.1073\/pnas.1012336107","type":"journal-article","created":{"date-parts":[[2010,10,14]],"date-time":"2010-10-14T21:06:00Z","timestamp":1287090360000},"page":"18850-18855","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":171,"title":["Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation"],"prefix":"10.1073","volume":"107","author":[{"given":"Valerie L.","family":"Anderson","sequence":"first","affiliation":[{"name":"School of Applied and Engineering Physics, Cornell University, Ithaca, NY; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trudy F.","family":"Ramlall","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Weill Cornell Medical College, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla C.","family":"Rospigliosi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Weill Cornell Medical College, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Watt W.","family":"Webb","sequence":"additional","affiliation":[{"name":"School of Applied and Engineering Physics, Cornell University, Ithaca, NY; 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