{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T23:16:53Z","timestamp":1790378213842,"version":"4.1.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T00:00:00Z","timestamp":1558310400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T00:00:00Z","timestamp":1558310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>There is still no successful strategy to treat Huntington\u2019s disease, an inherited autosomal disorder associated with the aggregation of mutated forms of the huntingtin protein containing polyglutamine tracts with more than 36 repeats. Recent experimental evidence is challenging the conventional view of the disease by revealing transcellular transfer of mutated huntingtin proteins which are able to seed oligomers involving wild type forms of the protein. Here we decipher the molecular mechanism of this unconventional heterogeneous oligomerization by performing discrete molecular dynamics simulations. We identify the most probable oligomer conformations and the molecular regions that can be targeted to destabilize them. Our computational findings are complemented experimentally by fluorescence-lifetime imaging microscopy\/fluorescence resonance energy transfer (FLIM-FRET) of cells co-transfected with huntingtin proteins containing short and large polyglutamine tracts. Our work clarifies the structural features responsible for heterogeneous huntingtin aggregation with possible implications to contrast the prion-like spreading of Huntington\u2019s disease.<\/jats:p>","DOI":"10.1038\/s41598-019-44151-0","type":"journal-article","created":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T10:03:37Z","timestamp":1558346617000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Molecular mechanisms of heterogeneous oligomerization of huntingtin proteins"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0323-8714","authenticated-orcid":false,"given":"Silvia","family":"Bonfanti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Chiara","family":"Lionetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Rita","family":"Fumagalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkat R.","family":"Chirasani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Tiana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8225-4025","authenticated-orcid":false,"given":"Nikolay V.","family":"Dokholyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5692-5465","authenticated-orcid":false,"given":"Stefano","family":"Zapperi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3010-8966","authenticated-orcid":false,"given":"Caterina A. M.","family":"La Porta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,5,20]]},"reference":[{"key":"44151_CR1","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/S0092-8674(00)80513-9","volume":"90","author":"SW Davies","year":"1997","unstructured":"Davies, S. W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the hd mutation. Cell 90, 537\u201348 (1997).","journal-title":"Cell"},{"key":"44151_CR2","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/S0140-6736(07)60111-1","volume":"369","author":"FO Walker","year":"2007","unstructured":"Walker, F. O. Huntington\u2019s disease. Lancet 369, 218\u201328 (2007).","journal-title":"Lancet"},{"key":"44151_CR3","first-page":"16","volume":"59","author":"DC Rubinsztein","year":"1996","unstructured":"Rubinsztein, D. C. et al. Phenotypic characterization of individuals with 30\u201340 cag repeats in the huntington disease (hd) gene reveals hd cases with 36 repeats and apparently normal elderly individuals with 36\u201339 repeats. American journal of human genetics 59, 16 (1996).","journal-title":"American journal of human genetics"},{"key":"44151_CR4","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1038\/nsmb.1992","volume":"18","author":"K Kar","year":"2011","unstructured":"Kar, K., Jayaraman, M., Sahoo, B., Kodali, R. & Wetzel, R. Critical nucleus size for disease-related polyglutamine aggregation is repeat-length dependent. Nat Struct Mol Biol 18, 328\u201336 (2011).","journal-title":"Nat Struct Mol Biol"},{"key":"44151_CR5","doi-asserted-by":"publisher","first-page":"4406","DOI":"10.1073\/pnas.1702237114","volume":"114","author":"M Chen","year":"2017","unstructured":"Chen, M. & Wolynes, P. G. Aggregation landscapes of huntingtin exon 1 protein fragments and the critical repeat length for the onset of huntington\u2019s disease. Proceedings of the National Academy of Sciences 114, 4406\u20134411 (2017).","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"44151_CR6","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/S0092-8674(00)81369-0","volume":"87","author":"L Mangiarini","year":"1996","unstructured":"Mangiarini, L. et al. Exon 1 of the hd gene with an expanded cag repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493\u2013506 (1996).","journal-title":"Cell"},{"key":"44151_CR7","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1016\/0896-6273(95)90346-1","volume":"14","author":"M DiFiglia","year":"1995","unstructured":"DiFiglia, M. et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14, 1075\u20131081 (1995).","journal-title":"Neuron"},{"key":"44151_CR8","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1038\/nn.3761","volume":"17","author":"E Pecho-Vrieseling","year":"2014","unstructured":"Pecho-Vrieseling, E. et al. Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons. Nat Neurosci 17, 1064\u201372 (2014).","journal-title":"Nat Neurosci"},{"key":"44151_CR9","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7768","volume":"6","author":"MMP Pearce","year":"2015","unstructured":"Pearce, M. M. P., Spartz, E. J., Hong, W., Luo, L. & Kopito, R. R. Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the drosophila brain. Nat Commun 6, 6768 (2015).","journal-title":"Nat Commun"},{"key":"44151_CR10","doi-asserted-by":"publisher","first-page":"E5427","DOI":"10.1073\/pnas.1516217112","volume":"112","author":"DT Babcock","year":"2015","unstructured":"Babcock, D. T. & Ganetzky, B. Transcellular spreading of huntingtin aggregates in the drosophila brain. Proc Natl Acad Sci USA 112, E5427\u201333 (2015).","journal-title":"Proc Natl Acad Sci USA"},{"key":"44151_CR11","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1016\/j.bbadis.2016.12.015","volume":"1863","author":"AHP Jansen","year":"2017","unstructured":"Jansen, A. H. P., Batenburg, K. L., Pecho-Vrieseling, E. & Reits, E. A. Visualization of prion-like transfer in huntington\u2019s disease models. Biochim Biophys Acta Mol Basis Dis 1863, 793\u2013800 (2017).","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"44151_CR12","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1002\/ana.24174","volume":"76","author":"F Cicchetti","year":"2014","unstructured":"Cicchetti, F. et al. Mutant huntingtin is present in neuronal grafts in huntington disease patients. Ann Neurol 76, 31\u201342 (2014).","journal-title":"Ann Neurol"},{"key":"44151_CR13","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1007\/s00401-016-1582-9","volume":"132","author":"I Jeon","year":"2016","unstructured":"Jeon, I. et al. Human-to-mouse prion-like propagation of mutant huntingtin protein. Acta Neuropathol 132, 577\u201392 (2016).","journal-title":"Acta Neuropathol"},{"key":"44151_CR14","doi-asserted-by":"publisher","first-page":"11884","DOI":"10.1073\/pnas.182276099","volume":"99","author":"S Chen","year":"2002","unstructured":"Chen, S., Ferrone, F. A. & Wetzel, R. Huntington\u2019s disease age-of-onset linked to polyglutamine aggregation nucleation. Proc Natl Acad Sci USA 99, 11884\u20139 (2002).","journal-title":"Proc Natl Acad Sci USA"},{"key":"44151_CR15","doi-asserted-by":"publisher","first-page":"15400","DOI":"10.1073\/pnas.0501651102","volume":"102","author":"AM Bhattacharyya","year":"2005","unstructured":"Bhattacharyya, A. M., Thakur, A. K. & Wetzel, R. polyglutamine aggregation nucleation: thermodynamics of a highly unfavorable protein folding reaction. Proc Natl Acad Sci USA 102, 15400\u20135 (2005).","journal-title":"Proc Natl Acad Sci USA"},{"key":"44151_CR16","doi-asserted-by":"publisher","first-page":"e1000772","DOI":"10.1371\/journal.pcbi.1000772","volume":"6","author":"VV Lakhani","year":"2010","unstructured":"Lakhani, V. V., Ding, F. & Dokholyan, N. V. Polyglutamine induced misfolding of huntingtin exon1 is modulated by the flanking sequences. PLoS Comput Biol 6, e1000772 (2010).","journal-title":"PLoS Comput Biol"},{"key":"44151_CR17","doi-asserted-by":"publisher","first-page":"15197","DOI":"10.1021\/jacs.6b08665","volume":"138","author":"M Chen","year":"2016","unstructured":"Chen, M., Tsai, M., Zheng, W. & Wolynes, P. G. The aggregation free energy landscapes of polyglutamine repeats. J Am Chem Soc 138, 15197\u201315203 (2016).","journal-title":"J Am Chem Soc"},{"key":"44151_CR18","doi-asserted-by":"publisher","first-page":"41452","DOI":"10.1074\/jbc.M303354200","volume":"278","author":"A Busch","year":"2003","unstructured":"Busch, A. et al. Mutant huntingtin promotes the fibrillogenesis of wild-type huntingtin: a potential mechanism for loss of huntingtin function in huntington\u2019s disease. J Biol Chem 278, 41452\u201361 (2003).","journal-title":"J Biol Chem"},{"key":"44151_CR19","doi-asserted-by":"publisher","first-page":"3579","DOI":"10.1021\/acs.biochem.7b00138","volume":"56","author":"JM Isas","year":"2017","unstructured":"Isas, J. M., Langen, A., Isas, M. C., Pandey, N. K. & Siemer, A. B. Formation and structure of wild type huntingtin exon-1 fibrils. Biochemistry 56, 3579\u20133586 (2017).","journal-title":"Biochemistry"},{"key":"44151_CR20","doi-asserted-by":"publisher","first-page":"11597","DOI":"10.1021\/jp206373g","volume":"115","author":"M D\u0142ugosz","year":"2011","unstructured":"D\u0142ugosz, M. & Trylska, J. Secondary structures of native and pathogenic huntingtin n-terminal fragments. The Journal of Physical Chemistry B 115, 11597\u201311608 (2011).","journal-title":"The Journal of Physical Chemistry B"},{"key":"44151_CR21","doi-asserted-by":"publisher","first-page":"e111","DOI":"10.1371\/journal.pone.0000111","volume":"1","author":"D Bulone","year":"2006","unstructured":"Bulone, D., Masino, L., Thomas, D. J., San Biagio, P. L. & Pastore, A. The interplay between polyq and protein context delays aggregation by forming a reservoir of protofibrils. PLoS One 1, e111 (2006).","journal-title":"PLoS One"},{"key":"44151_CR22","doi-asserted-by":"publisher","first-page":"17845","DOI":"10.1073\/pnas.1201811109","volume":"109","author":"S Piana","year":"2012","unstructured":"Piana, S., Lindorff-Larsen, K. & Shaw, D. E. Protein folding kinetics and thermodynamics from atomistic simulation. Proceedings of the National Academy of Sciences 109, 17845\u201317850 (2012).","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"44151_CR23","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1016\/j.str.2008.03.013","volume":"16","author":"F Ding","year":"2008","unstructured":"Ding, F., Tsao, D., Nie, H. & Dokholyan, N. V. Ab initio folding of proteins with all-atom discrete molecular dynamics. Structure 16, 1010\u20131018 (2008).","journal-title":"Structure"},{"key":"44151_CR24","first-page":"80","volume":"1","author":"EA Proctor","year":"2011","unstructured":"Proctor, E. A., Ding, F. & Dokholyan, N. V. Discrete molecular dynamics. Wiley Interdisciplinary Reviews: Computational Molecular Science 1, 80\u201392 (2011).","journal-title":"Wiley Interdisciplinary Reviews: Computational Molecular Science"},{"key":"44151_CR25","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/j.sbi.2006.01.001","volume":"16","author":"NV Dokholyan","year":"2006","unstructured":"Dokholyan, N. V. Studies of folding and misfolding using simplified models. Current opinion in structural biology 16, 79\u201385 (2006).","journal-title":"Current opinion in structural biology"},{"key":"44151_CR26","doi-asserted-by":"crossref","unstructured":"Gan, G., Ma, C. & Wu, J. Data clustering: theory, algorithms, and applications, vol. 20 (Siam, 2007).","DOI":"10.1137\/1.9780898718348"},{"key":"44151_CR27","doi-asserted-by":"publisher","first-page":"466 EP","DOI":"10.1038\/nmeth0607-466","volume":"4","author":"S Yin","year":"2007","unstructured":"Yin, S., Ding, F. & Dokholyan, N. V. Eris: an automated estimator of protein stability. Nature Methods 4, 466 EP, https:\/\/doi.org\/10.1038\/nmeth0607-466 (2007).","journal-title":"Nature Methods"},{"key":"44151_CR28","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1002\/mrd.22501","volume":"82","author":"C De Los Santos","year":"2015","unstructured":"De Los Santos, C., Chang, C.-W., Mycek, M.-A. & Cardullo, R. A. Frap, flim, and fret: detection and analysis of cellular dynamics on a molecular scale using fluorescence microscopy. Molecular reproduction and development 82, 587\u2013604 (2015).","journal-title":"Molecular reproduction and development"},{"key":"44151_CR29","doi-asserted-by":"publisher","first-page":"27","DOI":"10.3389\/fnmol.2016.00027","volume":"9","author":"T Zhao","year":"2016","unstructured":"Zhao, T., Hong, Y., Li, X.-J. & Li, S.-H. Subcellular clearance and accumulation of huntington disease protein: A mini-review. Front Mol Neurosci 9, 27 (2016).","journal-title":"Front Mol Neurosci"},{"key":"44151_CR30","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/S1474-4422(17)30037-6","volume":"16","author":"BE Stopschinski","year":"2017","unstructured":"Stopschinski, B. E. & Diamond, M. I. The prion model for progression and diversity of neurodegenerative diseases. Lancet Neurol 16, 323\u2013332 (2017).","journal-title":"Lancet Neurol"},{"key":"44151_CR31","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/S0009-2614(99)01123-9","volume":"314","author":"Y Sugita","year":"1999","unstructured":"Sugita, Y. & Okamoto, Y. Replica-exchange molecular dynamics method for protein folding. Chemical physics letters 314, 141\u2013151 (1999).","journal-title":"Chemical physics letters"},{"key":"44151_CR32","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1021\/ct700301q","volume":"4","author":"B Hess","year":"2008","unstructured":"Hess, B., Kutzner, C., Van Der Spoel, D. & Lindahl, E. Gromacs 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. Journal of chemical theory and computation 4, 435\u2013447 (2008).","journal-title":"Journal of chemical theory and computation"},{"key":"44151_CR33","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1002\/prot.340230412","volume":"23","author":"D Frishman","year":"1995","unstructured":"Frishman, D. & Argos, P. Knowledge-based protein secondary structure assignment. Proteins: Structure, Function, and Bioinformatics 23, 566\u2013579 (1995).","journal-title":"Proteins: Structure, Function, and Bioinformatics"},{"key":"44151_CR34","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","volume":"14","author":"W Humphrey","year":"1996","unstructured":"Humphrey, W., Dalke, A. & Schulten, K. Vmd: visual molecular dynamics. Journal of molecular graphics 14, 33\u201338 (1996).","journal-title":"Journal of molecular graphics"},{"key":"44151_CR35","doi-asserted-by":"publisher","first-page":"2445","DOI":"10.1093\/hmg\/ddq127","volume":"19","author":"X Li","year":"2010","unstructured":"Li, X. et al. Inhibiting the ubiquitin\u2013proteasome system leads to preferential accumulation of toxic n-terminal mutant huntingtin fragments. Human Molecular Genetics 19, 2445\u20132455, https:\/\/doi.org\/10.1093\/hmg\/ddq127 (2010).","journal-title":"Human Molecular Genetics"},{"key":"44151_CR36","unstructured":"Warren, S. et al. Rapid global fitting of large fluorescence lifetime imaging microscopy datasets. PLoS One 8 https:\/\/www.scopus.com\/inward\/record.uri?eid=2-s2.0-84881105876&doi=10.1371%2fjournal.pone.0070687&partnerID=40&md5=677816dede4fc243d224bdab7fc4e415 (2013)."},{"key":"44151_CR37","unstructured":"Schneider, C., Rasband, W. & Eliceiri, K. Nih image to imagej: 25 years of image analysis. Nature Methods 9, 671\u2013675, https:\/\/www.scopus.com\/inward\/record.uri?eid=2-s2.0-84863205849&doi=10.1038%2fnmeth.2089&partnerID=40&md5=27f8386cad59f4df66133961b6164bae (2012)."},{"key":"44151_CR38","unstructured":"Schindelin, J. et al. Fiji: An open-source platform for biological-image analysis. Nature Methods 9, 676\u2013682, https:\/\/www.scopus.com\/inward\/record.uri?eid=2-s2.0-84862520770&doi=10.1038%2fnmeth.2019&partnerID=40&md5=4f86c2ea85d9ca9f1539ffbfc2b7f403 (2012)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44151-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44151-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44151-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T09:42:36Z","timestamp":1671270156000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-44151-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,20]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["44151"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-44151-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,5,20]]},"assertion":[{"value":"14 February 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"7615"}}