{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T07:43:44Z","timestamp":1791877424218,"version":"4.3.4"},"reference-count":53,"publisher":"National Academy of Sciences","issue":"29","license":[{"start":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T00:00:00Z","timestamp":1657584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK-029023"],"award-info":[{"award-number":["DK-029023"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,7,19]]},"abstract":"<jats:p>\n                    The N-terminal region of the huntingtin protein, encoded by exon-1 (htt\n                    <jats:sup>ex1<\/jats:sup>\n                    ) and containing an expanded polyglutamine tract, forms fibrils that accumulate in neuronal inclusion bodies, resulting in Huntington\u2019s disease. We previously showed that reversible formation of a sparsely populated tetramer of the N-terminal amphiphilic domain, comprising a dimer of dimers in a four-helix bundle configuration, occurs on the microsecond timescale and is an essential prerequisite for subsequent nucleation and fibril formation that takes place orders of magnitude slower on a timescale of hours. For pathogenic htt\n                    <jats:sup>ex1<\/jats:sup>\n                    , such as htt\n                    <jats:sup>ex1<\/jats:sup>\n                    Q\n                    <jats:sub>35<\/jats:sub>\n                    with 35 glutamines, NMR signals decay too rapidly to permit measurement of time-intensive exchange-based experiments. Here, we show that quantitative analysis of both the kinetics and mechanism of prenucleation tetramerization and aggregation can be obtained simultaneously from a series of\n                    <jats:sup>1<\/jats:sup>\n                    H-\n                    <jats:sup>15<\/jats:sup>\n                    N band\u2013selective optimized flip-angle short-transient heteronuclear multiple quantum coherence (SOFAST-HMQC) correlation spectra. The equilibria and kinetics of tetramerization are derived from the time dependence of the\n                    <jats:sup>15<\/jats:sup>\n                    N chemical shifts and\n                    <jats:sup>1<\/jats:sup>\n                    H-\n                    <jats:sup>15<\/jats:sup>\n                    N cross-peak volume\/intensity ratios, while the kinetics of irreversible fibril formation are afforded by the decay curves of\n                    <jats:sup>1<\/jats:sup>\n                    H-\n                    <jats:sup>15<\/jats:sup>\n                    N cross-peak intensities and volumes. Analysis of data on htt\n                    <jats:sup>ex1<\/jats:sup>\n                    Q\n                    <jats:sub>35<\/jats:sub>\n                    over a series of concentrations ranging from 200 to 750 \u03bcM and containing variable (7 to 20%) amounts of the Met\n                    <jats:sup>7<\/jats:sup>\n                    O sulfoxide species, which does not tetramerize, shows that aggregation of native htt\n                    <jats:sup>ex1<\/jats:sup>\n                    Q\n                    <jats:sub>35<\/jats:sub>\n                    proceeds via fourth-order primary nucleation, consistent with the critical role of prenucleation tetramerization, coupled with first-order secondary nucleation. The Met\n                    <jats:sup>7<\/jats:sup>\n                    O sulfoxide species does not nucleate but is still incorporated into fibrils by elongation.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2207690119","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T14:35:24Z","timestamp":1657636524000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":29,"title":["Quantitative NMR analysis of the kinetics of prenucleation oligomerization and aggregation of pathogenic huntingtin exon-1 protein"],"prefix":"10.1073","volume":"119","author":[{"given":"Alberto","family":"Ceccon","sequence":"first","affiliation":[{"name":"Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, NlH, Bethesda, MD 20892-0520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5250-9149","authenticated-orcid":false,"given":"Vitali","family":"Tugarinov","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, NlH, Bethesda, MD 20892-0520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Torricella","sequence":"additional","affiliation":[{"name":"Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, NlH, Bethesda, MD 20892-0520"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3809-1027","authenticated-orcid":false,"given":"G. 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