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However, there are dozens of unique atomic-resolution structures of these aggregates, and such a highly polymorphic nature of the \u03b1-synuclein fibrils hampers efforts in disease-relevant in vitro studies on \u03b1-synuclein amyloid aggregation. In order to better understand the factors that affect polymorph selection, we studied the structures of \u03b1-synuclein fibrils in vitro as a function of pH and buffer using cryo-EM helical reconstruction. We find that in the physiological range of pH 5.8\u20137.4, a pH-dependent selection between Type 1, 2, and 3 polymorphs occurs. Our results indicate that even in the presence of seeds, the polymorph selection during aggregation is highly dependent on the buffer conditions, attributed to the non-polymorph-specific nature of secondary nucleation. We also uncovered two new polymorphs that occur at pH 7.0 in phosphate-buffered saline. The first is a monofilament Type 1 fibril that highly resembles the structure of the juvenile-onset synucleinopathy polymorph found in patient-derived material. The second is a new Type 5 polymorph that resembles a polymorph that has been recently reported in a study that used diseased tissues to seed aggregation. Taken together, our results highlight the shallow amyloid energy hypersurface that can be altered by subtle changes in the environment, including the pH which is shown to play a major role in polymorph selection and in many cases appears to be the determining factor in seeded aggregation. The results also suggest the possibility of producing disease-relevant structure in vitro.<\/jats:p>","DOI":"10.7554\/elife.93562","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T10:37:00Z","timestamp":1702636620000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.93562","source":"Crossref","is-referenced-by-count":25,"title":["On the pH-dependence of \u03b1-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation"],"prefix":"10.7554","volume":"12","author":[{"given":"Lukas","family":"Frey","sequence":"first","affiliation":[{"name":"Institute of Molecular Physical Science","place":["Z\u00fcrich, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Dhiman","family":"Ghosh","sequence":"first","affiliation":[{"name":"Institute of Molecular Physical Science","place":["Z\u00fcrich, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Bilal M","family":"Qureshi","sequence":"first","affiliation":[{"name":"Scientific Center for Optical and Electron Microscopy","place":["Z\u00fcrich, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"data-curation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"David","family":"Rhyner","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physical Science","place":["Z\u00fcrich, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3664-8277","authenticated-orcid":true,"given":"Ricardo","family":"Guerrero-Ferreira","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03czfpz43","id-type":"ROR","asserted-by":"publisher"}],"name":"Robert P. 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