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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,8,20]]},"abstract":"<jats:p>\n                    Amyloid formation by \u03b1-synuclein (\u03b1Syn) occurs in Parkinson\u2019s disease, multiple system atrophy, and dementia with Lewy bodies. Deciphering the residues that regulate \u03b1Syn amyloid fibril formation will not only provide mechanistic insight but may also reveal targets to prevent and treat disease. Previous investigations have identified several regions of \u03b1Syn to be important in the regulation of amyloid formation, including the non-amyloid-\u03b2 component (NAC), P1 region (residues 36 to 42), and residues in the C-terminal domain. Recent studies have also indicated the importance of the N-terminal region of \u03b1Syn for both its physiological and pathological roles. Here, the role of residues 2 to 7 in the N-terminal region of \u03b1Syn is investigated in terms of their ability to regulate amyloid fibril formation in vitro and in vivo. Deletion of these residues (\u03b1Syn\u0394N7) slows the rate of fibril formation in vitro and reduces the capacity of the protein to be recruited by wild-type (\u03b1SynWT) fibril seeds, despite cryo-EM showing a fibril structure consistent with those of full-length \u03b1Syn. Strikingly, fibril formation of \u03b1Syn\u0394N7 is not induced by liposomes, despite the protein binding to liposomes with similar affinity to \u03b1SynWT. A\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    model also showed that \u03b1Syn\u0394N7::YFP forms few puncta and lacks motility and lifespan defects typified by expression of \u03b1SynWT::YFP. Together, the results demonstrate the involvement of residues 2 to 7 of \u03b1Syn in amyloid formation, revealing a target for the design of amyloid inhibitors that may leave the functional role of the protein in membrane binding unperturbed.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2315006121","type":"journal-article","created":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T15:03:11Z","timestamp":1723474991000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":17,"title":["Residues 2 to 7 of \u03b1-synuclein regulate amyloid formation via lipid-dependent and lipid-independent pathways"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7196-7687","authenticated-orcid":false,"given":"Katherine M.","family":"Dewison","sequence":"first","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2415-6400","authenticated-orcid":false,"given":"Benjamin","family":"Rowlinson","sequence":"additional","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Machin","sequence":"additional","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6656-1578","authenticated-orcid":false,"given":"Joel A.","family":"Crossley","sequence":"additional","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dev","family":"Thacker","sequence":"additional","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5490-613X","authenticated-orcid":false,"given":"Martin","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine M.","family":"Ulamec","sequence":"additional","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1834-2485","authenticated-orcid":false,"given":"G. Nasir","family":"Khan","sequence":"additional","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3640-5275","authenticated-orcid":false,"given":"Neil A.","family":"Ranson","sequence":"additional","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5713-6457","authenticated-orcid":false,"given":"Patricija","family":"van Oosten-Hawle","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0802-5937","authenticated-orcid":false,"given":"David J.","family":"Brockwell","sequence":"additional","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheena E.","family":"Radford","sequence":"additional","affiliation":[{"name":"Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,8,12]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00501-z"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0298-106"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10795"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31828727ba"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-013-1096-7"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.276.5321.2045"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41531-020-0110-8"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.11.015"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-020-0384-x"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32687-1"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M008919200"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1039\/C8SC01109E"},{"key":"e_1_3_4_13_2","first-page":"1","article-title":"C-terminal truncation modulates \u03b1-synuclein\u2019s cytotoxicity and aggregation by promoting the interactions with membrane and chaperone","volume":"5","author":"Zhang C.","year":"2022","unstructured":"C. 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M. Dewison S. E. Radford Residues 2 to 7 of \u03b1-synuclein regulate amyloid formation via lipid-dependent and lipid-independent pathways (2023). https:\/\/doi.org\/10.5518\/1422 (Accessed 2 April 2024).","DOI":"10.1101\/2024.05.24.595537"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2315006121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,12]],"date-time":"2024-08-12T15:04:19Z","timestamp":1723475059000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2315006121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,12]]},"references-count":61,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2024,8,20]]}},"alternative-id":["10.1073\/pnas.2315006121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2315006121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,12]]},"assertion":[{"value":"2023-10-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2315006121"}}