{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:10:36Z","timestamp":1790878236187,"version":"4.1.0"},"reference-count":28,"publisher":"American Chemical Society (ACS)","issue":"28","license":[{"start":{"date-parts":[[2017,6,16]],"date-time":"2017-06-16T00:00:00Z","timestamp":1497571200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2017,6,16]],"date-time":"2017-06-16T00:00:00Z","timestamp":1497571200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2017,6,16]],"date-time":"2017-06-16T00:00:00Z","timestamp":1497571200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS084345"],"award-info":[{"award-number":["R01 NS084345"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006034","name":"University of Southern California","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006034","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM110521"],"award-info":[{"award-number":["R01 GM110521"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,7,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The fact that the heritable neurodegenerative disorder Huntington\u2019s disease (HD) is autosomal dominant means that there is one wild type and one mutant allele in most HD patients. The CAG repeat expansion in the exon 1 of the protein huntingtin (HTTex1) that causes the disease leads to the formation of HTT fibrils in vitro and vivo. An important question for understanding the molecular mechanism of HD is which role wild type HTT plays for the formation, propagation, and structure of these HTT fibrils. Here we report that fibrils of mutant HTTex1 are able to seed the aggregation of wild type HTTex1 into amyloid fibrils, which in turn can seed the fibril formation of mutant HTTex1. Solid-state NMR and electron paramagnetic resonance data showed that wild type HTTex1 fibrils closely resemble the structure of mutant fibrils, with small differences indicating a less extended fibril core. These data suggest that wild type fibrils can faithfully perpetuate the structure of mutant fibrils in HD. However, wild type HTTex1 monomers have a much higher equilibrium solubility compared to mutant HTTex1, and only a small fraction incorporates into fibrils.<\/jats:p>","DOI":"10.1021\/acs.biochem.7b00138","type":"journal-article","created":{"date-parts":[[2017,6,16]],"date-time":"2017-06-16T11:30:54Z","timestamp":1497612654000},"page":"3579-3586","source":"Crossref","is-referenced-by-count":39,"title":["Formation and Structure of Wild Type Huntingtin Exon\u20111\nFibrils"],"prefix":"10.1021","volume":"56","author":[{"given":"J. Mario","family":"Isas","sequence":"first","affiliation":[{"name":"University of Southern California , , , ,","place":["Los Angeles, California, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Langen","sequence":"additional","affiliation":[{"name":"University of Southern California , , , ,","place":["Los Angeles, California, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myles C.","family":"Isas","sequence":"additional","affiliation":[{"name":"University of Southern California , , , ,","place":["Los Angeles, California, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitin K.","family":"Pandey","sequence":"additional","affiliation":[{"name":"University of Southern California , , , ,","place":["Los Angeles, California, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0901-011X","authenticated-orcid":true,"given":"Ansgar B.","family":"Siemer","sequence":"additional","affiliation":[{"name":"University of Southern California , , , ,","place":["Los Angeles, California, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2017,6,16]]},"reference":[{"key":"2026081800070046900_cit1","doi-asserted-by":"publisher","first-page":"1990","DOI":"10.1126\/science.277.5334.1990","article-title":"Aggregation of huntingtin in neuronal\nintranuclear inclusions and dystrophic neurites in brain","volume":"277","author":"DiFiglia","year":"1997","journal-title":"Science"},{"key":"2026081800070046900_cit2","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.1073\/pnas.1221891110","article-title":"Aberrant\nsplicing of HTT generates the pathogenic exon 1 protein in Huntington\ndisease","volume":"110","author":"Sathasivam","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081800070046900_cit3","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1038\/nrg1691","article-title":"Diseases of unstable\nrepeat expansion: mechanisms and\ncommon principles","volume":"6","author":"Gatchel","year":"2005","journal-title":"Nat. Rev. Genet."},{"key":"2026081800070046900_cit4","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1212\/WNL.0b013e318249f683","article-title":"CAG repeat expansion in Huntington\ndisease determines age at onset in a fully dominant fashion","volume":"78","author":"Lee","year":"2012","journal-title":"Neurology"},{"key":"2026081800070046900_cit5","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/j.jmb.2011.12.010","article-title":"Slow amyloid\nnucleation\nvia \u03b1-helix-rich oligomeric intermediates in short polyglutamine-containing\nhuntingtin fragments","volume":"415","author":"Jayaraman","year":"2012","journal-title":"J. Mol. Biol."},{"key":"2026081800070046900_cit6","doi-asserted-by":"publisher","first-page":"91","DOI":"10.3390\/brainsci4010091","article-title":"Monomeric, oligomeric\nand polymeric proteins in huntington disease\nand other diseases of polyglutamine expansion","volume":"4","author":"Hoffner","year":"2014","journal-title":"Brain Sci."},{"key":"2026081800070046900_cit7","doi-asserted-by":"publisher","first-page":"9679","DOI":"10.1073\/pnas.0812083106","article-title":"Distinct conformations of in vitro and in vivo amyloids\nof huntingtin-exon1 show different cytotoxicity","volume":"106","author":"Nekooki-Machida","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081800070046900_cit8","doi-asserted-by":"publisher","first-page":"2894","DOI":"10.1016\/j.bpj.2012.04.050","article-title":"Fibrillar \u03b1-synuclein\nand huntingtin exon 1 assemblies are toxic to the cells","volume":"102","author":"Pieri","year":"2012","journal-title":"Biophys. J."},{"key":"2026081800070046900_cit9","doi-asserted-by":"publisher","first-page":"31739","DOI":"10.1074\/jbc.M112.353839","article-title":"Structural features and domain organization of huntingtin\nfibrils","volume":"287","author":"Bugg","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2026081800070046900_cit10","doi-asserted-by":"publisher","first-page":"4558","DOI":"10.1021\/ja110715f","article-title":"The aggregation-enhancing huntingtin N-terminus is\nhelical in amyloid fibrils","volume":"133","author":"Sivanandam","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"2026081800070046900_cit11","doi-asserted-by":"publisher","first-page":"6653","DOI":"10.1021\/bi501010q","article-title":"Polyglutamine\namyloid core boundaries\nand flanking domain dynamics in huntingtin fragment fibrils determined\nby solid-state nuclear magnetic resonance","volume":"53","author":"Hoop","year":"2014","journal-title":"Biochemistry"},{"key":"2026081800070046900_cit12","doi-asserted-by":"publisher","first-page":"3942","DOI":"10.1021\/acs.biochem.5b00281","article-title":"Solid-State\nNuclear Magnetic Resonance\non the Static and Dynamic Domains of Huntingtin Exon-1 Fibrils","volume":"54","author":"Isas","year":"2015","journal-title":"Biochemistry"},{"key":"2026081800070046900_cit13","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1073\/pnas.1521933113","article-title":"Huntingtin exon 1 fibrils feature\nan interdigitated \u03b2-hairpin-based polyglutamine core","volume":"113","author":"Hoop","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081800070046900_cit14","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.jmb.2011.06.045","article-title":"Structural characterization\nof polyglutamine fibrils\nby solid-state NMR spectroscopy","volume":"412","author":"Schneider","year":"2011","journal-title":"J. Mol. Biol."},{"key":"2026081800070046900_cit15","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.jmb.2016.12.010","article-title":"Backbone Engineering within a Latent\n\u03b2-Hairpin\nStructure to Design Inhibitors of Polyglutamine Amyloid Formation","volume":"429","author":"Kar","year":"2017","journal-title":"J. Mol. Biol."},{"key":"2026081800070046900_cit16","doi-asserted-by":"publisher","first-page":"5591","DOI":"10.1073\/pnas.042681399","article-title":"Amyloid fibers\nare\nwater-filled nanotubes","volume":"99","author":"Perutz","year":"2002","journal-title":"Proc. Natl. Acad. Sci.\nU. S. A."},{"key":"2026081800070046900_cit17","doi-asserted-by":"publisher","first-page":"12605","DOI":"10.1073\/pnas.0900678106","article-title":"Single\nhomopolypeptide chains collapse into mechanically rigid conformations","volume":"106","author":"Dougan","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026081800070046900_cit18","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1021\/bm0494388","article-title":"New model for crystalline\npolyglutamine assemblies\nand their connection with amyloid fibrils","volume":"6","author":"Sikorski","year":"2005","journal-title":"Biomacromolecules"},{"key":"2026081800070046900_cit19","doi-asserted-by":"publisher","first-page":"15462","DOI":"10.1038\/ncomms15462","article-title":"Fibril polymorphism affects immobilized non-amyloid\nflanking domains of huntingtin exon1 rather than its polyglutamine\ncore","volume":"8","author":"Lin","year":"2017","journal-title":"Nat. Commun."},{"key":"2026081800070046900_cit20","doi-asserted-by":"publisher","first-page":"41452","DOI":"10.1074\/jbc.M303354200","article-title":"Mutant huntingtin promotes the fibrillogenesis of wild-type\nhuntingtin: a potential mechanism for loss of huntingtin function\nin Huntington\u2019s disease","volume":"278","author":"Busch","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2026081800070046900_cit21","doi-asserted-by":"publisher","first-page":"6951","DOI":"10.1063\/1.470372","article-title":"Heteronuclear\ndecoupling in rotating solids","volume":"103","author":"Bennett","year":"1995","journal-title":"J. Chem. Phys."},{"key":"2026081800070046900_cit22","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/S0009-2614(01)00791-6","article-title":"13C\u20131H\ndipolar-assisted rotational\nresonance in magic-angle spinning NMR","volume":"344","author":"Takegoshi","year":"2001","journal-title":"Chem.\nPhys. Lett."},{"key":"2026081800070046900_cit23","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1002\/mrc.2225","article-title":"Further Conventions for NMR Shielding and Chemical\nShifts (IUPAC Recommendations 2008)","volume":"46","author":"Harris","year":"2008","journal-title":"Magn. Reson.\nChem."},{"key":"2026081800070046900_cit24","doi-asserted-by":"publisher","first-page":"12709","DOI":"10.1021\/bi050927h","article-title":"Thermodynamics of A\nbeta(1\u201340) amyloid fibril elongation","volume":"44","author":"O\u2019Nuallain","year":"2005","journal-title":"Biochemistry"},{"key":"2026081800070046900_cit25","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1016\/j.jmb.2006.01.041","article-title":"Alanine scanning mutagenesis of Abeta(1\u201340)\namyloid fibril stability","volume":"357","author":"Williams","year":"2006","journal-title":"J. Mol. 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Rep."}],"container-title":["Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.biochem.7b00138","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/56\/28\/3579\/16002951\/bi7b00138.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/bichaw\/article-pdf\/56\/28\/3579\/16002951\/bi7b00138.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:42:45Z","timestamp":1787042565000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/bichaw\/article\/56\/28\/3579\/810883\/Formation-and-Structure-of-Wild-Type-Huntingtin"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,16]]},"references-count":28,"journal-issue":{"issue":"28","published-online":{"date-parts":[[2017,6,16]]},"published-print":{"date-parts":[[2017,7,18]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.biochem.7b00138","relation":{},"ISSN":["0006-2960","1520-4995"],"issn-type":[{"value":"0006-2960","type":"print"},{"value":"1520-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,16]]}}}