{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:39:05Z","timestamp":1760060345419,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T00:00:00Z","timestamp":1755820800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Telethon","doi-asserted-by":"publisher","award":["TCP15011"],"award-info":[{"award-number":["TCP15011"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Huntington\u2019s Disease (HD) originates from the expansion of a polyglutamine (PolyQ) tract in the huntingtin protein (Htt), which can assume a coiled-coil fold (Cc). We previously found that Cc structures mediate the aggregation and toxicity of polyQ Htt. Since polyQ Htt aggregates were previously found to be internalized by cells, here we hypothesize that Cc structures might be implicated in the intercellular propagation of Htt aggregates. To test this hypothesis, we performed experiments using human cell lines expressing Htt proteins with different probabilities to acquire a Cc fold. We found that Htt with reduced Cc structures were released significantly less compared to Htt with intact Cc structures. We also found that Cc structures mediate the internalization of Htt proteins in recipient cells. Together, these results underline the importance of the Cc structure in the process of intercellular propagation of Htt polyQ aggregates and suggest that interfering with Cc formation might be a therapeutic strategy for HD.<\/jats:p>","DOI":"10.3390\/ijms26178162","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T13:47:49Z","timestamp":1755870469000},"page":"8162","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Coiled-Coil Structures Mediate the Intercellular Propagation of Huntingtin"],"prefix":"10.3390","volume":"26","author":[{"given":"Marco","family":"Bosica","sequence":"first","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Grasselli","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Panfili","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7415-9936","authenticated-orcid":false,"given":"Franca","family":"Orsini","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2429-8967","authenticated-orcid":false,"given":"Luana","family":"Fioriti","sequence":"additional","affiliation":[{"name":"Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy"},{"name":"Department of Cell Biology and Pathology, Columbia University, New York, NY 10032, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1212\/WNL.0b013e3181bd1121","article-title":"Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease","volume":"73","author":"Aziz","year":"2009","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15005","DOI":"10.1038\/nrdp.2015.5","article-title":"Huntington disease","volume":"1","author":"Bates","year":"2015","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"26","DOI":"10.4161\/pri.1.1.4056","article-title":"Aggregation of Expanded Huntingtin in the Brains of Patients with Huntington Disease","volume":"1","author":"Hoffner","year":"2007","journal-title":"Prion"},{"key":"ref_4","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":"ref_5","doi-asserted-by":"crossref","first-page":"3493","DOI":"10.1007\/s00415-021-10418-8","article-title":"Huntington\u2019s disease: Lessons from prion disorders","volume":"268","author":"Alpaugh","year":"2021","journal-title":"J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"E5427","DOI":"10.1073\/pnas.1516217112","article-title":"Transcellular spreading of huntingtin aggregates in the Drosophila brain","volume":"112","author":"Babcock","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/ncb1830","article-title":"Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates","volume":"11","author":"Ren","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1093\/brain\/awq328","article-title":"Neuronal degeneration in striatal transplants and Huntington\u2019s disease: Potential mechanisms and clinical implications","volume":"134","author":"Cicchetti","year":"2011","journal-title":"Brain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1007\/s13311-012-0112-2","article-title":"Huntington\u2019s Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of Disease","volume":"9","author":"Ehrlich","year":"2012","journal-title":"Neurotherapeutics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/nn.3761","article-title":"Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons","volume":"17","author":"Rieker","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Dinamarca, M.C., Colombo, L., Brykczynska, U., Grimm, A., Fruh, I., Hossain, I., Gabriel, D., Eckert, A., M\u00fcller, M., and Pecho-Vrieseling, E. (2023). Transmission-selective muscle pathology induced by the active propagation of mutant huntingtin across the human neuromuscular synapse. Front. Mol. Neurosci., 16.","DOI":"10.3389\/fnmol.2023.1287510"},{"key":"ref_12","unstructured":"Abounit, S., Delage, E., and Zurzolo, C. (2001). Identification and Characterization of Tunneling Nanotubes for Intercellular Trafficking. Current Protocols in Cell Biology, John Wiley & Sons, Inc.. Available online: http:\/\/onlinelibrary.wiley.com.ezproxy.cul.columbia.edu\/doi\/10.1002\/0471143030.cb1210s67\/abstract."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20121898","article-title":"The cell biology of prion-like spread of protein aggregates: Mechanisms and implication in neurodegeneration","volume":"452","author":"Costanzo","year":"2013","journal-title":"Biochem. J."},{"key":"ref_14","first-page":"3678","article-title":"Transfer of polyglutamine aggregates in neuronal cells occurs in tunneling nanotubes","volume":"126","author":"Costanzo","year":"2013","journal-title":"J. Cell. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s00401-016-1582-9","article-title":"Human-to-mouse prion-like propagation of mutant huntingtin protein","volume":"132","author":"Jeon","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.cell.2010.11.042","article-title":"Essential role of coiled coils for aggregation and activity of Q\/N-rich prions and PolyQ proteins","volume":"143","author":"Fiumara","year":"2010","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1002\/cbic.200300781","article-title":"Coiled Coil Domains: Stability, Specificity, and Biological Implications","volume":"5","author":"Mason","year":"2004","journal-title":"ChemBioChem"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.jsb.2008.01.016","article-title":"Fifty years of coiled-coils and \u03b1-helical bundles: A close relationship between sequence and structure","volume":"163","author":"Parry","year":"2008","journal-title":"J. Struct. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"21576","DOI":"10.1074\/jbc.M401074200","article-title":"Stabilizing and Destabilizing Clusters in the Hydrophobic Core of Long Two-stranded \u03b1-Helical Coiled-coils","volume":"279","author":"Kwok","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1093\/nass\/nrn234","article-title":"Regulation of protein-protein interaction via assembly of coiled-coil domain","volume":"52","author":"Suzuki","year":"2008","journal-title":"Nucleic Acids Symp. Ser."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6738","DOI":"10.1021\/bi500449a","article-title":"Role of the Coiled-Coil Structural Motif in Polyglutamine Aggregation","volume":"53","author":"Kokona","year":"2014","journal-title":"Biochemistry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1002\/bies.201300001","article-title":"Aggregation of polyQ-extended proteins is promoted by interaction with their natural coiled-coil partners: Insights &amp; Perspectives","volume":"35","author":"Petrakis","year":"2013","journal-title":"BioEssays"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Batlle, C., Calvo, I., Iglesias, V., Lynch, C.J., Gil-Garcia, M., Serrano, M., and Ventura, S. (2021). MED15 prion-like domain forms a coiled-coil responsible for its amyloid conversion and propagation. Commun. Biol., 4.","DOI":"10.1038\/s42003-021-01930-8"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9746","DOI":"10.1039\/C4SM01801J","article-title":"Coiled coil driven membrane fusion between cyclodextrin vesicles and liposomes","volume":"10","author":"Versluis","year":"2014","journal-title":"Soft Matter"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8297","DOI":"10.1074\/jbc.M111.324483","article-title":"Trimeric, coiled-coil extension on peptide fusion inhibitor of HIV-1 influences selection of resistance pathways","volume":"287","author":"Zhuang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.ceb.2014.05.004","article-title":"Biogenesis and Secretion of Exosomes","volume":"29","author":"Kowal","year":"2014","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1006\/jsbi.1999.4182","article-title":"Proline Affects Oligomerization of a Coiled Coil by Inducing a Kink in a Long Helix","volume":"128","author":"Chang","year":"1999","journal-title":"J. Struct. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1016\/j.neuron.2015.05.021","article-title":"The Persistence of Hippocampal-Based Memory Requires Protein Synthesis Mediated by the Prion-like Protein CPEB3","volume":"86","author":"Fioriti","year":"2015","journal-title":"Neuron"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1016\/j.celrep.2015.04.061","article-title":"SUMOylation Is an Inhibitory Constraint that Regulates the Prion-like Aggregation and Activity of CPEB3","volume":"11","author":"Drisaldi","year":"2015","journal-title":"Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1016\/j.celrep.2015.04.060","article-title":"The CPEB3 Protein Is a Functional Prion that Interacts with the Actin Cytoskeleton","volume":"11","author":"Stephan","year":"2015","journal-title":"Cell Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ab.2009.08.001","article-title":"Single-step detection of mutant huntingtin in animal and human tissues: A bioassay for Huntington\u2019s disease","volume":"395","author":"Weiss","year":"2009","journal-title":"Anal. Biochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.mcn.2004.09.006","article-title":"The neurotoxicity of prion protein (PrP) peptide 106-126 is independent of the expression level of PrP and is not mediated by abnormal PrP species","volume":"28","author":"Fioriti","year":"2005","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11320","DOI":"10.1074\/jbc.M412441200","article-title":"Cytosolic prion protein (PrP) is not toxic in N2a cells and primary neurons expressing pathogenic PrP mutations","volume":"280","author":"Fioriti","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1111\/j.1600-0854.2004.00247.x","article-title":"Exosomes: A bubble ride for prions?","volume":"6","author":"Vilette","year":"2005","journal-title":"Traffic"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Chivet, M., Hemming, F., Pernet-Gallay, K., Fraboulet, S., and Sadoul, R. (2012). Emerging Role of Neuronal Exosomes in the Central Nervous System. Front. Physio., 3.","DOI":"10.3389\/fphys.2012.00145"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1042\/BST20120266","article-title":"Exosomes as a novel way of interneuronal communication","volume":"41","author":"Chivet","year":"2013","journal-title":"Biochem. Soc. Trans."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1080\/19336896.2016.1223003","article-title":"Tunneling nanotubes: A possible highway in the spreading of tau and other prion-like proteins in neurodegenerative diseases","volume":"10","author":"Abounit","year":"2016","journal-title":"Prion"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.neuron.2012.02.017","article-title":"Intercellular (Mis)communication in Neurodegenerative Disease","volume":"73","author":"Garden","year":"2012","journal-title":"Neuron"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41380-021-01350-4","article-title":"Prion-like properties of the mutant huntingtin protein in living organisms: The evidence and the relevance","volume":"27","author":"Alpaugh","year":"2022","journal-title":"Mol. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e58499","DOI":"10.7554\/eLife.58499","article-title":"Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses","volume":"9","author":"Donnelly","year":"2020","journal-title":"Elife"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6768","DOI":"10.1038\/ncomms7768","article-title":"Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain","volume":"6","author":"Pearce","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Bartl, S., Oueslati, A., Southwell, A.L., Siddu, A., Parth, M., David, L.S., Maxan, A., Salhat, N., Burkert, M., and Mairhofer, A. (2020). Inhibiting cellular uptake of mutant huntingtin using a monoclonal antibody: Implications for the treatment of Huntington\u2019s disease. Neurobiol. Dis., 141.","DOI":"10.1016\/j.nbd.2020.104943"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9000","DOI":"10.1523\/JNEUROSCI.0118-17.2017","article-title":"Mutant Huntingtin Is Secreted via a Late Endosomal\/Lysosomal Unconventional Secretory Pathway","volume":"37","author":"Trajkovic","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1080\/19336896.2021.1961569","article-title":"Decoding the role of coiled-coil motifs in human prion-like proteins","volume":"15","author":"Behbahanipour","year":"2021","journal-title":"Prion"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Cheng, H., and Sablitzky, F. (2019). The coiled coil domain of DEF6 facilitates formation of large vesicle-like, cytoplasmic aggregates that trap the P-body marker DCP1 and exhibit prion-like features. bioRxiv.","DOI":"10.1101\/538082"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Gerlich, D.W. (2017). Cell organization by liquid phase separation. Nat. Rev. Mol. Cell Biol., 18.","DOI":"10.1038\/nrm.2017.93"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1523\/JNEUROSCI.1656-20.2020","article-title":"Liquid-Liquid Phase Separation in Physiology and Pathophysiology of the Nervous System","volume":"41","author":"Hayashi","year":"2021","journal-title":"J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ford, L.K., and Fioriti, L. (2020). Coiled-Coil Motifs of RNA-Binding Proteins: Dynamicity in RNA Regulation. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.607947"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/978-3-540-72843-6_19","article-title":"Pharmacological interference with protein-protein interactions mediated by coiled-coil motifs","volume":"186","author":"Strauss","year":"2008","journal-title":"Handb. Exp. Pharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8162\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:34:04Z","timestamp":1760034844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,22]]},"references-count":49,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178162"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178162","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,8,22]]}}}