{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T20:34:50Z","timestamp":1780691690813,"version":"3.54.1"},"reference-count":125,"publisher":"Frontiers Media SA","issue":"17","license":[{"start":{"date-parts":[[2019,6,15]],"date-time":"2019-06-15T00:00:00Z","timestamp":1560556800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01 AG019322"],"award-info":[{"award-number":["R01 AG019322"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM112678"],"award-info":[{"award-number":["R01GM112678"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Exp Biol Med (Maywood)"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:p>Huntington\u2019s disease, like other neurodegenerative diseases, continues to lack an effective cure. Current treatments that address early symptoms ultimately fail Huntington\u2019s disease patients and their families, with the disease typically being fatal within 10\u201315 years from onset. Huntington\u2019s disease is an inherited disorder with motor and mental impairment, and is associated with the genetic expansion of a CAG codon repeat encoding a polyglutamine-segment-containing protein called huntingtin. These Huntington\u2019s disease mutations cause misfolding and aggregation of fragments of the mutant huntingtin protein, thereby likely contributing to disease toxicity through a combination of gain-of-toxic-function for the misfolded aggregates and a loss of function from sequestration of huntingtin and other proteins. As with other amyloid diseases, the mutant protein forms non-native fibrillar structures, which in Huntington\u2019s disease are found within patients\u2019 neurons. The intracellular deposits are associated with dysregulation of vital processes, and inter-neuronal transport of aggregates may contribute to disease progression. However, a molecular understanding of these aggregates and their detrimental effects has been frustrated by insufficient structural data on the misfolded protein state. In this review, we examine recent developments in the structural biology of polyglutamine-expanded huntingtin fragments, and especially the contributions enabled by advances in solid-state nuclear magnetic resonance spectroscopy. We summarize and discuss our current structural understanding of the huntingtin deposits and how this information furthers our understanding of the misfolding mechanism and disease toxicity mechanisms.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Impact statement<\/jats:title>\n                    <jats:p>Many incurable neurodegenerative disorders are associated with, and potentially caused by, the amyloidogenic misfolding and aggregation of proteins. Usually, complex genetic and behavioral factors dictate disease risk and age of onset. Due to its principally mono-genic origin, which strongly predicts the age-of-onset by the extent of CAG repeat expansion, Huntington\u2019s disease (HD) presents a unique opportunity to dissect the underlying disease-causing processes in molecular detail. Yet, until recently, the mutant huntingtin protein with its expanded polyglutamine domain has resisted structural study at the atomic level. We present here a review of recent developments in HD structural biology, facilitated by breakthrough data from solid-state NMR spectroscopy, electron microscopy, and complementary methods. The misfolded structures of the fibrillar proteins inform our mechanistic understanding of the disease-causing molecular processes in HD, other CAG repeat expansion disorders, and, more generally, protein deposition disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/1535370219856620","type":"journal-article","created":{"date-parts":[[2019,6,15]],"date-time":"2019-06-15T12:49:23Z","timestamp":1560602963000},"page":"1584-1595","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":53,"title":["Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington\u2019s disease"],"prefix":"10.3389","volume":"244","author":[{"given":"Irina","family":"Matlahov","sequence":"first","affiliation":[{"name":"Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5390-3321","authenticated-orcid":false,"given":"Patrick CA","family":"van der Wel","sequence":"additional","affiliation":[{"name":"Department of Structural Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA"},{"name":"Zernike Institute for Advanced Materials, University of Groningen, Groningen 9747 AG, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2019,6,15]]},"reference":[{"key":"bibr1-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-061516-045115"},{"key":"bibr2-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.ssnmr.2017.10.001"},{"key":"bibr3-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/nature23002"},{"key":"bibr4-1535370219856620","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.36402"},{"key":"bibr5-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/35000576"},{"key":"bibr6-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"bibr7-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.02.003"},{"key":"bibr8-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/nature25502"},{"key":"bibr9-1535370219856620","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00145"},{"key":"bibr10-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/nature03916"},{"key":"bibr11-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2009.08.002"},{"key":"bibr12-1535370219856620","doi-asserted-by":"publisher","DOI":"10.4161\/pri.23807"},{"key":"bibr13-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1313668110"},{"key":"bibr14-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1301342110"},{"key":"bibr15-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2008.06561.x"},{"key":"bibr16-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.11.042"},{"key":"bibr17-1535370219856620","volume":"18","author":"Kwon MJ","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"bibr18-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.15.9158"},{"key":"bibr19-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.221451398"},{"key":"bibr20-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu504"},{"key":"bibr21-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5334.1990"},{"key":"bibr22-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.1999.0454"},{"key":"bibr23-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1221891110"},{"key":"bibr24-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1097\/nen.0b013e318040b2c8"},{"key":"bibr25-1535370219856620","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-130050"},{"key":"bibr26-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-71779-1_2"},{"key":"bibr27-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.08.009"},{"key":"bibr28-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/srep00895"},{"key":"bibr29-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/cb500335w"},{"key":"bibr30-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.12.013"},{"key":"bibr31-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/nature02998"},{"key":"bibr32-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15462"},{"key":"bibr33-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80514-0"},{"key":"bibr34-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2001.4850"},{"key":"bibr35-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.nano.2004.11.004"},{"key":"bibr36-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.016923"},{"key":"bibr37-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1097\/00001756-200110290-00042"},{"key":"bibr38-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1570"},{"key":"bibr39-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1700"},{"key":"bibr40-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0604547103"},{"key":"bibr41-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl440"},{"key":"bibr42-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm217"},{"key":"bibr43-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2009.01.032"},{"key":"bibr44-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2011.12.010"},{"key":"bibr45-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2013.06.030"},{"key":"bibr46-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2015.03.021"},{"key":"bibr47-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2005.10.053"},{"key":"bibr48-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.09.023"},{"key":"bibr49-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20112175"},{"key":"bibr50-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2012.01.030"},{"key":"bibr51-1535370219856620","doi-asserted-by":"publisher","DOI":"10.2174\/157340911793743574"},{"key":"bibr52-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-014-8932-1"},{"key":"bibr53-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/0960-9822(93)90174-M"},{"key":"bibr54-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.12.5355"},{"key":"bibr55-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1002\/prot.20602"},{"key":"bibr56-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1521933113"},{"key":"bibr57-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.042681399"},{"key":"bibr58-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/bm0494388"},{"key":"bibr59-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(99)00933-3"},{"key":"bibr60-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0812083106"},{"key":"bibr61-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1401587111"},{"key":"bibr62-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/bi300551b"},{"key":"bibr63-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.603332"},{"key":"bibr64-1535370219856620","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.00710"},{"key":"bibr65-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2018.03.017"},{"key":"bibr66-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06761-6"},{"key":"bibr67-1535370219856620","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.18065"},{"key":"bibr68-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(02)02335-9"},{"key":"bibr69-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.182393899"},{"key":"bibr70-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.06.044"},{"key":"bibr71-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2011.06.045"},{"key":"bibr72-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2016.04.022"},{"key":"bibr73-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b10893"},{"key":"bibr74-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.004808"},{"key":"bibr75-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biophys-083012-130356"},{"key":"bibr76-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1042\/ETLS20170088"},{"key":"bibr77-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/ja110715f"},{"key":"bibr78-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2013.01.016"},{"key":"bibr79-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.5b00281"},{"key":"bibr80-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/bi501010q"},{"key":"bibr81-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/nature03680"},{"key":"bibr82-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b09002"},{"key":"bibr83-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200804198"},{"key":"bibr84-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2012.09.011"},{"key":"bibr85-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b02619"},{"key":"bibr86-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.7b00138"},{"key":"bibr87-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.03.017"},{"key":"bibr88-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2014.06.002"},{"key":"bibr89-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2011.04.022"},{"key":"bibr90-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3194"},{"key":"bibr91-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.6b10624"},{"key":"bibr92-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.353839"},{"key":"bibr93-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.8b09213"},{"key":"bibr94-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/srep19180"},{"key":"bibr95-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.446237"},{"key":"bibr96-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501651102"},{"key":"bibr97-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C114.552943"},{"key":"bibr98-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b08665"},{"key":"bibr99-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.1992"},{"key":"bibr100-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/jp305065c"},{"key":"bibr101-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2014.02.027"},{"key":"bibr102-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/ng0197-62"},{"key":"bibr103-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-71779-1_7"},{"key":"bibr104-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205809200"},{"key":"bibr105-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1038\/nature01301"},{"key":"bibr106-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.252577"},{"key":"bibr107-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M704789200"},{"key":"bibr108-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.04.007"},{"key":"bibr109-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/bi3000929"},{"key":"bibr110-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81782-1"},{"key":"bibr111-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0503634102"},{"key":"bibr112-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.23.2905"},{"key":"bibr113-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2012.04.050"},{"key":"bibr114-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2013.11.019"},{"key":"bibr115-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.07.032"},{"key":"bibr116-1535370219856620","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2017.00647"},{"key":"bibr117-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.182426899"},{"key":"bibr118-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0914773107"},{"key":"bibr119-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.170280697"},{"key":"bibr120-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.421685"},{"key":"bibr121-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.03.017"},{"key":"bibr122-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200909067"},{"key":"bibr123-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.013193"},{"key":"bibr124-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.11.020"},{"key":"bibr125-1535370219856620","doi-asserted-by":"publisher","DOI":"10.1021\/bi011772q"}],"container-title":["Experimental Biology and Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1535370219856620","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/1535370219856620","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/1535370219856620","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T17:50:27Z","timestamp":1777571427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ebm-journal.org\/journals\/experimental-biology-and-medicine\/articles\/10.1177\/1535370219856620\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,15]]},"references-count":125,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["10.1177\/1535370219856620"],"URL":"https:\/\/doi.org\/10.1177\/1535370219856620","relation":{},"ISSN":["1535-3702","1535-3699"],"issn-type":[{"value":"1535-3702","type":"print"},{"value":"1535-3699","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,15]]}}}