{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:17:02Z","timestamp":1760239022705,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T00:00:00Z","timestamp":1600646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Huntington\u2019s disease is a progressive, autosomal dominant, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. As a result, the translated protein, huntingtin, contains an abnormally long polyglutamine stretch that makes it prone to misfold and aggregating. Aggregation of huntingtin is believed to be the cause of Huntington\u2019s disease. However, understanding on how, and why, huntingtin aggregates are deleterious has been hampered by lack of enough relevant structural data. In this review, we discuss our recent findings on a glutamine-based functional amyloid isolated from Drosophila brain and how this information provides plausible structural insight on the structure of huntingtin deposits in the brain.<\/jats:p>","DOI":"10.3390\/ijms21186910","type":"journal-article","created":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T08:18:01Z","timestamp":1600676281000},"page":"6910","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Implications of the Orb2 Amyloid Structure in Huntington\u2019s Disease"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6393-6058","authenticated-orcid":false,"given":"Rub\u00e9n","family":"Herv\u00e1s","sequence":"first","affiliation":[{"name":"Stowers Institute for Medical Research, Kansas City, MO 64110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexey G.","family":"Murzin","sequence":"additional","affiliation":[{"name":"MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kausik","family":"Si","sequence":"additional","affiliation":[{"name":"Stowers Institute for Medical Research, Kansas City, MO 64110, USA"},{"name":"Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1146\/annurev.neuro.29.051605.113042","article-title":"Trinucleotide Repeat Disorders","volume":"30","author":"Orr","year":"2007","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/35000576","article-title":"Motor disorder in Huntington\u2019s disease begins as a dysfunction in error feedback control","volume":"403","author":"Smith","year":"2000","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.neuron.2016.02.003","article-title":"The Biology of Huntingtin","volume":"89","author":"Saudou","year":"2016","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nature25502","article-title":"The cryo-electron microscopy structure of huntingtin","volume":"555","author":"Guo","year":"2018","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes","volume":"72","author":"MacDonald","year":"1993","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"12784","DOI":"10.1073\/pnas.221451398","article-title":"Caspase 3-cleaved N-terminal fragments of wild-type and mutant huntingtin are present in normal and Huntington\u2019s disease brains, associate with membranes, and undergo calpaindependent proteolysis","volume":"98","author":"Kim","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0092-8674(00)80514-0","article-title":"Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo","volume":"90","author":"Scherzinger","year":"1997","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1097\/nen.0b013e318040b2c8","article-title":"Characterization of Huntingtin Pathologic Fragments in Human Huntington Disease, Transgenic Mice, and Cell Models","volume":"66","author":"Schilling","year":"2007","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3233\/JHD-130050","article-title":"Large genetic animal models of huntington\u2019s disease","volume":"2","author":"Howland","year":"2013","journal-title":"J. Huntingt. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/978-3-319-71779-1_2","article-title":"Genetic rodent models of huntington disease","volume":"Volume 1049","author":"Novati","year":"2018","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1021\/acs.biochem.6b00936","article-title":"Proteins Containing Expanded Polyglutamine Tracts and Neurodegenerative Disease","volume":"56","author":"Adegbuyiro","year":"2017","journal-title":"Biochemistry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1126\/science.1056784","article-title":"Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity","volume":"291","author":"Nucifora","year":"2001","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1126\/science.292.5521.1552","article-title":"Impairment of the ubiquitin-proteasome system by protein aggregation","volume":"292","author":"Bence","year":"2001","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1007\/s12035-014-8932-1","article-title":"Polyglutamine Aggregation in Huntington Disease: Does Structure Determine Toxicity?","volume":"52","author":"Hoffner","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.nbd.2018.08.019","article-title":"Mutational analysis implicates the amyloid fibril as the toxic entity in Huntington\u2019s disease","volume":"120","author":"Drombosky","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/nature03680","article-title":"Structure of the cross-\u03b2 spine of amyloid-like fibrils","volume":"435","author":"Nelson","year":"2005","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/0022-2836(68)90014-4","article-title":"\u201cCross-\u03b2\u201d conformation in proteins","volume":"32","author":"Geddes","year":"1968","journal-title":"J. Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nsmb.1570","article-title":"Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism","volume":"16","author":"Thakur","year":"2009","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1016\/j.jmb.2009.12.017","article-title":"Modulation of Polyglutamine Conformations and Dimer Formation by the N-Terminus of Huntingtin","volume":"396","author":"Williamson","year":"2010","journal-title":"J. Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1093\/hmg\/ddl440","article-title":"The first 17 amino acids of Huntingtin modulate its sub-cellular localization, aggregation and effects on calcium homeostasis","volume":"16","author":"Rockabrand","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Atwal, R.S., Xia, J., Pinchev, D., Taylor, J., Epand, R.M., and Truant, R. (2007). Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. Hum. Mol. Genet., 16.","DOI":"10.1093\/hmg\/ddm217"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.jmb.2005.10.053","article-title":"Oligoproline effects on polyglutamine conformation and aggregation","volume":"355","author":"Bhattacharyya","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.jmb.2007.09.023","article-title":"Flanking Polyproline Sequences Inhibit \u03b2-Sheet Structure in Polyglutamine Segments by Inducing PPII-like Helix Structure","volume":"374","author":"Darnell","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/prot.20602","article-title":"Polyglutamine homopolymers having 8-45 residues form slablike \u03b2-crystallite assemblies","volume":"61","author":"Sharma","year":"2005","journal-title":"Proteins Struct. Funct. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.jmb.2011.06.045","article-title":"Structural characterization of polyglutamine fibrils by solid-state NMR spectroscopy","volume":"412","author":"Schneider","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4558","DOI":"10.1021\/ja110715f","article-title":"The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils","volume":"133","author":"Sivanandam","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"45470","DOI":"10.1074\/jbc.M107502200","article-title":"Intra- and Intermolecular \u03b2-Pleated Sheet Formation in Glutamine-repeat Inserted Myoglobin as a Model for Polyglutamine Diseases","volume":"276","author":"Tanaka","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14576","DOI":"10.1021\/jacs.8b09002","article-title":"Structural Fingerprinting of Protein Aggregates by Dynamic Nuclear Polarization-Enhanced Solid-State NMR at Natural Isotopic Abundance","volume":"140","author":"Smith","year":"2018","journal-title":"J. Am. Chem. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0014-5793(99)00933-3","article-title":"Peptide models for inherited neurodegenerative disorders: Conformation and aggregation properties of long polyglutamine peptides with and without interruptions","volume":"456","author":"Sharma","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9679","DOI":"10.1073\/pnas.0812083106","article-title":"Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity","volume":"106","author":"Kurosawa","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5796","DOI":"10.1073\/pnas.1401587111","article-title":"Structural motif of polyglutamine amyloid fibrils discerned with mixed-isotope infrared spectroscopy","volume":"111","author":"Buchanan","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5822","DOI":"10.1021\/bi300551b","article-title":"UV resonance raman spectroscopy monitors polyglutamine backbone and side chain hydrogen bonding and fibrillization","volume":"51","author":"Xiong","year":"2012","journal-title":"Biochemistry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2560","DOI":"10.1074\/jbc.M114.603332","article-title":"Molecular interaction between the chaperone Hsc70 and the N-terminal flank of huntingtin exon 1 modulates aggregation","volume":"290","author":"Monsellier","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"31739","DOI":"10.1074\/jbc.M112.353839","article-title":"Structural features and domain organization of huntingtin fibrils","volume":"287","author":"Bugg","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.cell.2017.08.009","article-title":"In Situ Architecture and Cellular Interactions of PolyQ Inclusions","volume":"171","author":"Saha","year":"2017","journal-title":"Cell"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Herv\u00e1s, R., Li, L., Majumdar, A., del Fern\u00e1ndez-Ram\u00edrez, M.C., Unruh, J.R., Slaughter, B.D., Galera-Prat, A., Santana, E., Suzuki, M., and Nagai, Y. (2016). Molecular Basis of Orb2 Amyloidogenesis and Blockade of Memory Consolidation. PLoS Biol., 14.","DOI":"10.1371\/journal.pbio.1002361"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1038\/nn1996","article-title":"Function of the Drosophila CPEB protein Orb2 in long-term courtship memory","volume":"10","author":"Keleman","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1016\/j.celrep.2015.05.037","article-title":"Synaptic Orb2A Bridges Memory Acquisition and Late Memory Consolidation in Drosophila","volume":"11","author":"Dag","year":"2015","journal-title":"Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.neuron.2012.08.028","article-title":"Drosophila CPEB Orb2A Mediates Memory Independent of Its RNA-Binding Domain","volume":"76","author":"Stepien","year":"2012","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.cell.2012.01.004","article-title":"Critical role of amyloid-like oligomers of Drosophila Orb2 in the persistence of memory","volume":"148","author":"Majumdar","year":"2012","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1016\/j.cub.2016.09.054","article-title":"A Putative Biochemical Engram of Long-Term Memory","volume":"26","author":"Li","year":"2016","journal-title":"Curr. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1126\/science.aba3526","article-title":"Cryo-EM structure of a neuronal functional amyloid implicated in memory persistence in Drosophila","volume":"367","author":"Hervas","year":"2020","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1073\/pnas.1521933113","article-title":"Huntingtin exon 1 fibrils feature an interdigitated \u03b2-hairpin-based polyglutamine core","volume":"113","author":"Hoop","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep38265","article-title":"Identification and Structural Characterization of the N-terminal Amyloid Core of Orb2 isoform A","volume":"6","author":"Cervantes","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1016\/j.bpj.2011.04.022","article-title":"Structural formation of huntingtin exon 1 aggregates probed by small-angle neutron scattering","volume":"100","author":"Stanley","year":"2011","journal-title":"Biophys. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.bpj.2014.06.002","article-title":"Investigating the structural impact of the glutamine repeat in huntingtin assembly","volume":"107","author":"Perevozchikova","year":"2014","journal-title":"Biophys. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms15462","article-title":"Fibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core","volume":"8","author":"Lin","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/978-3-319-71779-1_7","article-title":"Spinocerebellum ataxia type 6: Molecular mechanisms and calcium channel genetics","volume":"Volume 1049","author":"Du","year":"2018","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Boatz, J.C., Piretra, T., Lasorsa, A., Matlahov, I., Conway, J.F., and van der Wel, P.C.A. (2020). Protofilament structure and supramolecular polymorphism of aggregated mutant huntingtin exon 1. J. Mol. Biol.","DOI":"10.1016\/j.jmb.2020.06.021"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/18\/6910\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:11:54Z","timestamp":1760177514000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/18\/6910"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,21]]},"references-count":49,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijms21186910"],"URL":"https:\/\/doi.org\/10.3390\/ijms21186910","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2020,9,21]]}}}