{"language":[{"iso":"eng"}],"intvolume":"        11","title":"Identification of on- and off-pathway oligomers in amyloid fibril formation","scopus_import":"1","quality_controlled":"1","main_file_link":[{"url":"https://pubs.rsc.org/en/content/articlehtml/2020/sc/c9sc06501f","open_access":"1"}],"oa_version":"Published Version","issue":"24","keyword":["general chemistry"],"pmid":1,"day":"08","tmp":{"legal_code_url":"https://creativecommons.org/licenses/by-nc/3.0/legalcode","image":"/images/cc_by_nc.png","short":"CC BY-NC (3.0)","name":"Creative Commons Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0)"},"publisher":"Royal Society of Chemistry","year":"2020","article_type":"original","license":"https://creativecommons.org/licenses/by-nc/3.0/","date_published":"2020-06-08T00:00:00Z","type":"journal_article","extern":"1","volume":11,"date_updated":"2021-11-26T11:21:20Z","publication_identifier":{"eissn":["2041-6539"],"issn":["2041-6520"]},"author":[{"last_name":"Dear","first_name":"Alexander J.","full_name":"Dear, Alexander J."},{"full_name":"Meisl, Georg","first_name":"Georg","last_name":"Meisl"},{"orcid":"0000-0002-7854-2139","full_name":"Šarić, Anđela","first_name":"Anđela","id":"bf63d406-f056-11eb-b41d-f263a6566d8b","last_name":"Šarić"},{"first_name":"Thomas C. T.","full_name":"Michaels, Thomas C. T.","last_name":"Michaels"},{"last_name":"Kjaergaard","first_name":"Magnus","full_name":"Kjaergaard, Magnus"},{"first_name":"Sara","full_name":"Linse, Sara","last_name":"Linse"},{"last_name":"Knowles","full_name":"Knowles, Tuomas P. J.","first_name":"Tuomas P. J."}],"doi":"10.1039/c9sc06501f","_id":"10350","abstract":[{"lang":"eng","text":"The misfolding and aberrant aggregation of proteins into fibrillar structures is a key factor in some of the most prevalent human diseases, including diabetes and dementia. Low molecular weight oligomers are thought to be a central factor in the pathology of these diseases, as well as critical intermediates in the fibril formation process, and as such have received much recent attention. Moreover, on-pathway oligomeric intermediates are potential targets for therapeutic strategies aimed at interrupting the fibril formation process. However, a consistent framework for distinguishing on-pathway from off-pathway oligomers has hitherto been lacking and, in particular, no consensus definition of on- and off-pathway oligomers is available. In this paper, we argue that a non-binary definition of oligomers' contribution to fibril-forming pathways may be more informative and we suggest a quantitative framework, in which each oligomeric species is assigned a value between 0 and 1 describing its relative contribution to the formation of fibrils. First, we clarify the distinction between oligomers and fibrils, and then we use the formalism of reaction networks to develop a general definition for on-pathway oligomers, that yields meaningful classifications in the context of amyloid formation. By applying these concepts to Monte Carlo simulations of a minimal aggregating system, and by revisiting several previous studies of amyloid oligomers in light of our new framework, we demonstrate how to perform these classifications in practice. For each oligomeric species we obtain the degree to which it is on-pathway, highlighting the most effective pharmaceutical targets for the inhibition of amyloid fibril formation."}],"publication_status":"published","publication":"Chemical Science","article_processing_charge":"No","acknowledgement":"We are grateful to the Schiff Foundation (AJD), Peterhouse, Cambridge (TCTM), the Swiss National Science foundation (TCTM), Ramon Jenkins Fellowship, Sidney Sussex, Cambridge (GM), the Royal Society (AŠ), the Academy of Medical Sciences and Wellcome Trust (AŠ), the Danish Research Council (MK), the Lundbeck Foundation (MK), the Swedish Research Council (SL), the Wellcome Trust (TPJK), the Cambridge Centre for Misfolding Diseases (TPJK), the BBSRC (TPJK), the Frances and Augustus Newman Foundation (TPJK) for financial support. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) through the ERC grants PhysProt (agreement no. 337969), MAMBA (agreement no. 340890) and NovoNordiskFonden (SL).","date_created":"2021-11-26T09:08:19Z","month":"06","citation":{"ama":"Dear AJ, Meisl G, Šarić A, et al. Identification of on- and off-pathway oligomers in amyloid fibril formation. <i>Chemical Science</i>. 2020;11(24):6236-6247. doi:<a href=\"https://doi.org/10.1039/c9sc06501f\">10.1039/c9sc06501f</a>","mla":"Dear, Alexander J., et al. “Identification of On- and off-Pathway Oligomers in Amyloid Fibril Formation.” <i>Chemical Science</i>, vol. 11, no. 24, Royal Society of Chemistry, 2020, pp. 6236–47, doi:<a href=\"https://doi.org/10.1039/c9sc06501f\">10.1039/c9sc06501f</a>.","short":"A.J. Dear, G. Meisl, A. Šarić, T.C.T. Michaels, M. Kjaergaard, S. Linse, T.P.J. Knowles, Chemical Science 11 (2020) 6236–6247.","ieee":"A. J. Dear <i>et al.</i>, “Identification of on- and off-pathway oligomers in amyloid fibril formation,” <i>Chemical Science</i>, vol. 11, no. 24. Royal Society of Chemistry, pp. 6236–6247, 2020.","ista":"Dear AJ, Meisl G, Šarić A, Michaels TCT, Kjaergaard M, Linse S, Knowles TPJ. 2020. Identification of on- and off-pathway oligomers in amyloid fibril formation. Chemical Science. 11(24), 6236–6247.","chicago":"Dear, Alexander J., Georg Meisl, Anđela Šarić, Thomas C. T. Michaels, Magnus Kjaergaard, Sara Linse, and Tuomas P. J. Knowles. “Identification of On- and off-Pathway Oligomers in Amyloid Fibril Formation.” <i>Chemical Science</i>. Royal Society of Chemistry, 2020. <a href=\"https://doi.org/10.1039/c9sc06501f\">https://doi.org/10.1039/c9sc06501f</a>.","apa":"Dear, A. J., Meisl, G., Šarić, A., Michaels, T. C. T., Kjaergaard, M., Linse, S., &#38; Knowles, T. P. J. (2020). Identification of on- and off-pathway oligomers in amyloid fibril formation. <i>Chemical Science</i>. Royal Society of Chemistry. <a href=\"https://doi.org/10.1039/c9sc06501f\">https://doi.org/10.1039/c9sc06501f</a>"},"external_id":{"pmid":["32953019"]},"page":"6236-6247","status":"public","oa":1,"user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9"}