{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T16:00:10Z","timestamp":1775923210634,"version":"3.50.1"},"reference-count":49,"publisher":"Portland Press Ltd.","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,8,18]]},"abstract":"<jats:p>PolyQ (polyglutamine) diseases such as HD (Huntington's disease) or SCA1 (spinocerebellar ataxia type 1) are neurodegenerative disorders caused by abnormally elongated polyQ tracts in human proteins. PolyQ expansions promote misfolding and aggregation of disease-causing proteins, leading to the appearance of nuclear and cytoplasmic inclusion bodies in patient neurons. Several lines of experimental evidence indicate that this process is critical for disease pathogenesis. However, the molecular mechanisms underlying spontaneous polyQ-containing aggregate formation and the perturbation of neuronal processes are still largely unclear. The present chapter reviews the current literature regarding misfolding and aggregation of polyQ-containing disease proteins. We specifically focus on studies that have investigated the amyloidogenesis of polyQ-containing HTTex1 (huntingtin exon 1) fragments. These protein fragments are disease-relevant and play a critical role in HD pathogenesis. We outline potential mechanisms behind mutant HTTex1 aggregation and toxicity, as well as proteins and small molecules that can modify HTTex1 amyloidogenesis in vitro and in vivo. The potential implications of such studies for the development of novel therapeutic strategies are discussed.<\/jats:p>","DOI":"10.1042\/bse0560167","type":"journal-article","created":{"date-parts":[[2014,8,18]],"date-time":"2014-08-18T11:18:39Z","timestamp":1408360719000},"page":"167-180","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures"],"prefix":"10.1042","volume":"56","author":[{"given":"Philipp","family":"Trepte","sequence":"additional","affiliation":[{"name":"Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Roessle-Str. 10, 13125 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine","family":"Strempel","sequence":"additional","affiliation":[{"name":"Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Roessle-Str. 10, 13125 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erich E.","family":"Wanker","sequence":"additional","affiliation":[{"name":"Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Robert-Roessle-Str. 10, 13125 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2014,8,18]]},"reference":[{"key":"2021111610195893800_B1","doi-asserted-by":"crossref","first-page":"4273","DOI":"10.1093\/nar\/gks011","article-title":"Evolution and function of CAG\/polyglutamine repeats in protein-protein interaction networks","volume":"40","author":"Schaefer","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2021111610195893800_B2","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1515\/BC-2011-252","article-title":"Polyglutamine tracts as modulators of transcriptional activation from yeast to mammals","volume":"393","author":"Atanesyan","year":"2012","journal-title":"Biol. Chem."},{"key":"2021111610195893800_B3","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1128\/MCB.01140-07","article-title":"Functional conservation of the glutamine-rich domains of yeast Gal11 and human SRC-1 in the transactivation of glucocorticoid receptor Tau 1 in Saccharomyces cerevisiae","volume":"28","author":"Kim","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"2021111610195893800_B4","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.bbagrm.2008.05.008","article-title":"Polyglutamine gene function and dysfunction in the ageing brain","volume":"1779","author":"Hands","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"2021111610195893800_B5","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1096\/fasebj.3.9.2568302","article-title":"Location cloning strategy for characterizing genetic defects in Huntington's disease and Alzheimer's disease","volume":"3","author":"Gusella","year":"1989","journal-title":"FASEB J."},{"key":"2021111610195893800_B6","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's disease chromosomes","volume":"72","author":"The Huntington's Disease Collaborative Research Group","year":"1993","journal-title":"Cell"},{"key":"2021111610195893800_B7","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/ng1095-115","article-title":"HEAT repeats in the Huntington's disease protein","volume":"11","author":"Andrade","year":"1995","journal-title":"Nat. Genet."},{"key":"2021111610195893800_B8","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1093\/hmg\/7.9.1463","article-title":"Huntingtin interacts with a family of WW domain proteins","volume":"7","author":"Faber","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"2021111610195893800_B9","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/nrn1806","article-title":"Normal huntingtin function: an alternative approach to Huntington's disease","volume":"6","author":"Cattaneo","year":"2005","journal-title":"Nat. Rev."},{"key":"2021111610195893800_B10","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1126\/science.277.5334.1990","article-title":"Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain","volume":"277","author":"DiFiglia","year":"1997","journal-title":"Science"},{"key":"2021111610195893800_B11","doi-asserted-by":"crossref","first-page":"3076","DOI":"10.1073\/pnas.0708931105","article-title":"Asymmetric segregation of protein aggregates is associated with cellular aging and rejuvenation","volume":"105","author":"Lindner","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111610195893800_B12","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S0092-8674(00)80513-9","article-title":"Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation","volume":"90","author":"Davies","year":"1997","journal-title":"Cell"},{"key":"2021111610195893800_B13","doi-asserted-by":"crossref","first-page":"4604","DOI":"10.1073\/pnas.96.8.4604","article-title":"Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology","volume":"96","author":"Scherzinger","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111610195893800_B14","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":"2021111610195893800_B15","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1073\/pnas.1221891110","article-title":"Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease","volume":"110","author":"Sathasivam","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111610195893800_B16","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1091\/mbc.12.5.1393","article-title":"Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation","volume":"12","author":"Waelter","year":"2001","journal-title":"Mol. Biol. Cell"},{"key":"2021111610195893800_B17","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1006\/exnr.1998.7005","article-title":"Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein","volume":"156","author":"Sieradzan","year":"1999","journal-title":"Exp. Neurol."},{"key":"2021111610195893800_B18","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/srep00895","article-title":"Cellular inclusion bodies of mutant huntingtin exon 1 obscure small fibrillar aggregate species","volume":"2","author":"Sahl","year":"2012","journal-title":"Sci. Rep."},{"key":"2021111610195893800_B19","doi-asserted-by":"crossref","first-page":"2894","DOI":"10.1016\/j.bpj.2012.04.050","article-title":"Fibrillar \u03b1-synuclein and huntingtin exon 1 assemblies are toxic to the cells","volume":"102","author":"Pieri","year":"2012","journal-title":"Biophys. J."},{"key":"2021111610195893800_B20","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/S0968-0004(03)00168-3","article-title":"The hunt for huntingtin function: interaction partners tell many different stories","volume":"28","author":"Harjes","year":"2003","journal-title":"Trends Biochem. Sci."},{"key":"2021111610195893800_B21","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.cell.2010.11.050","article-title":"Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions","volume":"144","author":"Olzscha","year":"2011","journal-title":"Cell"},{"key":"2021111610195893800_B22","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1038\/nm1066","article-title":"Protein aggregation and neurodegenerative disease","volume":"10","author":"Ross","year":"2004","journal-title":"Nat. Med."},{"key":"2021111610195893800_B23","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/0092-8674(93)90635-4","article-title":"Seeding \u201cone-dimensional crystallization\u201d of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie?","volume":"73","author":"Jarrett","year":"1993","journal-title":"Cell"},{"key":"2021111610195893800_B24","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1038\/nsmb860","article-title":"Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer","volume":"11","author":"Wacker","year":"2004","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2021111610195893800_B25","doi-asserted-by":"crossref","first-page":"21807","DOI":"10.1074\/jbc.M109.084434","article-title":"Tracking mutant huntingtin aggregation kinetics in cells reveals three major populations that include an invariant oligomer pool","volume":"285","author":"Olshina","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2021111610195893800_B26","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/nature07195","article-title":"Misfolded proteins partition between two distinct quality control compartments","volume":"454","author":"Kaganovich","year":"2008","journal-title":"Nature"},{"key":"2021111610195893800_B27","doi-asserted-by":"crossref","first-page":"3588","DOI":"10.1091\/mbc.e13-06-0315","article-title":"The Hsp70\/90 cochaperone, Sti1, suppresses proteotoxicity by regulating spatial quality control of amyloid-like proteins","volume":"24","author":"Wolfe","year":"2013","journal-title":"Mol. Biol. Cell"},{"key":"2021111610195893800_B28","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1038\/nn.2528","article-title":"Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease","volume":"13","author":"Martinez-Vicente","year":"2010","journal-title":"Nat. Neurosci."},{"key":"2021111610195893800_B29","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1083\/jcb.200709080","article-title":"Impaired ubiquitin-proteasome system activity in the synapses of Huntington's disease mice","volume":"180","author":"Wang","year":"2008","journal-title":"J. Cell Biol."},{"key":"2021111610195893800_B30","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/nn.2346","article-title":"Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin","volume":"12","author":"Morfini","year":"2009","journal-title":"Nat. Neurosci."},{"key":"2021111610195893800_B31","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1093\/hmg\/11.9.1137","article-title":"Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin","volume":"11","author":"Wyttenbach","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2021111610195893800_B32","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/sj.cdd.4401528","article-title":"Amyloid \u03b2 induces neuronal cell death through ROS-mediated ASK1 activation","volume":"12","author":"Kadowaki","year":"2005","journal-title":"Cell Death Diff."},{"key":"2021111610195893800_B33","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1093\/hmg\/11.23.2905","article-title":"Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells","volume":"11","author":"Yang","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2021111610195893800_B34","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1023\/B:SCAM.0000007124.19463.e5","article-title":"Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat","volume":"24","author":"Huang","year":"1998","journal-title":"Cell Mol. Genet."},{"key":"2021111610195893800_B35","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1038\/ncb1478","article-title":"Cytosolic chaperonin prevents polyglutamine toxicity with altering the aggregation state","volume":"8","author":"Kitamura","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"2021111610195893800_B36","doi-asserted-by":"crossref","first-page":"11635","DOI":"10.1074\/jbc.M412042200","article-title":"Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes","volume":"280","author":"Jana","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021111610195893800_B37","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/nbt.1608","article-title":"Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein","volume":"28","author":"Bauer","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"2021111610195893800_B38","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nature11866","article-title":"Identification of a candidate therapeutic autophagy-inducing peptide","volume":"494","author":"Shoji-Kawata","year":"2013","journal-title":"Nature"},{"key":"2021111610195893800_B39","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.cell.2009.03.018","article-title":"Acetylation targets mutant huntingtin to autophagosomes for degradation","volume":"137","author":"Jeong","year":"2009","journal-title":"Cell"},{"key":"2021111610195893800_B40","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1093\/hmg\/10.12.1307","article-title":"Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease","volume":"10","author":"Sittler","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"2021111610195893800_B41","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nchembio.1140","article-title":"Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation","volume":"9","author":"Wang","year":"2013","journal-title":"Nat. Chem. Biol."},{"key":"2021111610195893800_B42","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nchembio.763","article-title":"Small-molecule proteostasis regulators for protein conformational diseases","volume":"8","author":"Calamini","year":"2012","journal-title":"Nat. Chem. Biol."},{"key":"2021111610195893800_B43","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nchembio883","article-title":"Small molecules enhance autophagy and reduce toxicity in Huntington's disease models","volume":"3","author":"Sarkar","year":"2007","journal-title":"Nat. Chem. Biol."},{"key":"2021111610195893800_B44","doi-asserted-by":"crossref","first-page":"16982","DOI":"10.1073\/pnas.1004498107","article-title":"A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model","volume":"107","author":"Tsvetkov","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111610195893800_B45","doi-asserted-by":"crossref","first-page":"6739","DOI":"10.1073\/pnas.110138997","article-title":"Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington's disease therapy","volume":"97","author":"Heiser","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111610195893800_B46","doi-asserted-by":"crossref","first-page":"16400","DOI":"10.1073\/pnas.182426599","article-title":"Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay","volume":"99","author":"Heiser","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111610195893800_B47","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1093\/hmg\/ddl210","article-title":"Green tea (\u2212)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models","volume":"15","author":"Ehrnhoefer","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"2021111610195893800_B48","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1146\/annurev.genet.39.110304.095804","article-title":"Drosophila as a model for human neurodegenerative disease","volume":"39","author":"Bilen","year":"2005","journal-title":"Annu. Rev. Genet."},{"key":"2021111610195893800_B49","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nsmb.1437","article-title":"EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers","volume":"15","author":"Ehrnhoefer","year":"2008","journal-title":"Nat. Struct. Mol. Biol."}],"container-title":["Essays in Biochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/essaysbiochem\/article-pdf\/doi\/10.1042\/bse0560167\/736132\/bse0560167.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/essaysbiochem\/article-pdf\/doi\/10.1042\/bse0560167\/736132\/bse0560167.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T10:32:22Z","timestamp":1637058742000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/essaysbiochem\/article\/doi\/10.1042\/bse0560167\/78399\/Spontaneous-self-assembly-of-pathogenic-huntingtin"}},"subtitle":[],"editor":[{"given":"Sarah","family":"Perrett","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2014,8,18]]},"references-count":49,"URL":"https:\/\/doi.org\/10.1042\/bse0560167","relation":{},"ISSN":["0071-1365","1744-1358"],"issn-type":[{"value":"0071-1365","type":"print"},{"value":"1744-1358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,8,18]]}}}