{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:44:52Z","timestamp":1791834292155,"version":"4.3.4"},"reference-count":108,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Huntington's Disease"],"abstract":"<jats:p>\n                    Huntington's Disease (HD) is a progressive neurodegenerative disease that is caused by a CAG-repeat expansion in the exon 1 of the huntingtin (\n                    <jats:italic toggle=\"yes\">HTT<\/jats:italic>\n                    ) gene, which results in the formation of toxic mutant HTT (mHTT) exon 1 fragments with expanded polyglutamine (polyQ) stretch. These mHTT fragments are prone to misfolding and aggregation, causing cytotoxicity, particularly in the striatal neurons. The lack of disease-modifying treatments for HD emphasizes the need to develop new therapeutic strategies to prevent or reverse HD pathology. The reduction of the mHTT exon 1 fragment by facilitating its selective degradation may be a promising approach to prevent aggregation, thereby delaying or preventing the onset of HD. Since the ubiquitin-proteasome system (UPS) is not impaired in HD, enabling strategies to selectively target mHTT towards the UPS or autophagy would improve mHTT clearance. In this review, we describe three main strategies to modulate mHTT levels. First, we discuss different ubiquitin-modifying enzymes that have been associated with HTT and may act as possible therapeutic targets. Next, we focus on more targeted approaches for the selective degradation of mHTT with engineered small molecule compounds such as PROTACs and AUTOTACs. Finally, we summarize the current knowledge of HTT-specific intracellular antibodies (intrabodies) as potential candidates for gene therapy. Together, this review aims to assess different possible avenues for the treatment of HD.\n                  <\/jats:p>","DOI":"10.1177\/18796397261494078","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:10:26Z","timestamp":1791551426000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Directing mutant huntingtin towards degradation: Strategies and therapeutic opportunities"],"prefix":"10.1177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4316-9669","authenticated-orcid":false,"given":"Florence DM","family":"Wavreil","sequence":"first","affiliation":[{"name":"Amsterdam UMC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Schipper-Krom","sequence":"additional","affiliation":[{"name":"Amsterdam UMC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2258-5639","authenticated-orcid":false,"given":"Eric AJ","family":"Reits","sequence":"additional","affiliation":[{"name":"Amsterdam UMC"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.11.038"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1221891110"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-024-00801-2"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a024240"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awag040"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(10)70245-3"},{"key":"e_1_3_2_9_2","first-page":"141","article-title":"Emerging therapies for Huntington\u2019s disease - focus on N-terminal Huntingtin and Huntingtin exon 1","volume":"16","author":"van der Bent ML","year":"2022","unstructured":"van der Bent ML, Evers MM, Vall\u00e8s A. Emerging therapies for Huntington\u2019s disease - focus on N-terminal Huntingtin and Huntingtin exon 1. Biologics 2022; 16: 141\u2013160.","journal-title":"Biologics"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5334.1990"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.5.1393"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600426"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(04)00151-0"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2004.12.021"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.486076"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-19538-0"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2013.11.023"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092194"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2015.00001"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.RA119.001486"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2007667117"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2527258122"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2018.11"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2014.09.003"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2020.101203"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-019-0099-1"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11152262"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2023.1107323"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mmr.2026.100032"},{"key":"e_1_3_2_30_2","article-title":"E3 ubiquitin ligases: structures, biological functions, diseases, and therapy","volume":"6","author":"Wang H","year":"2025","unstructured":"Wang H, et al. E3 ubiquitin ligases: structures, biological functions, diseases, and therapy. MedComm (2020) 2025; 6: e70528.","journal-title":"MedComm (2020)"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1402215111"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M706620200"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu343"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.371724"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-017-0853-3"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2023.148081"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.07.003"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05320-3"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2016.03.027"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.187591"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2006.10.031"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M809739200"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adl2036"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3001-05.2005"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412042200"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M601603200"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1710549114"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2018.01.006"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu317"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.889166"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-13711-7"},{"key":"e_1_3_2_52_2","article-title":"Cytoplasmic ubiquitin-specific protease 19 (USP19) modulates aggregation of polyglutamine-expanded ataxin-3 and Huntingtin through the HSP90 chaperone","volume":"11","author":"He WT","year":"2016","unstructured":"He WT, et al. Cytoplasmic ubiquitin-specific protease 19 (USP19) modulates aggregation of polyglutamine-expanded ataxin-3 and Huntingtin through the HSP90 chaperone. PLoS One 2016; 11: e0147515.","journal-title":"PLoS One"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212235200"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2009.05.039"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E20-11-0747"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1111\/neup.12840"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI134565"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05653-z"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.141230798"},{"key":"e_1_3_2_60_2","first-page":"607","article-title":"Chemical-mediated targeted protein degradation in neurodegenerative diseases","volume":"11","author":"Hyun S","year":"2021","unstructured":"Hyun S, Shin D. Chemical-mediated targeted protein degradation in neurodegenerative diseases. Life (Basel) 2021; 11: 607.","journal-title":"Life (Basel)"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1080\/17568919.2025.2463310"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.37349\/etat.2023.00194"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201706529"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2018.01.012"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c14078"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2545-9"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1039\/D2CS00624C"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c01712"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.09.009"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28520-4"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2026.118585"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.medp.2023.100004"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1722-1"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2015.01.003"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1608"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddtec.2019.01.002"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1134\/S0006297925604034"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2021.1915979"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104569"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104619"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1080\/14737175.2024.2314183"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0029199"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005727"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.071058398"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2004.11.003"},{"key":"e_1_3_2_86_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbrainres.2003.11.011"},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0505321102"},{"key":"e_1_3_2_88_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2015.03.021"},{"key":"e_1_3_2_89_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07-099689"},{"key":"e_1_3_2_90_2","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e3181f530ec"},{"key":"e_1_3_2_91_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.022631799"},{"key":"e_1_3_2_92_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.016923"},{"key":"e_1_3_2_93_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2747-08.2008"},{"key":"e_1_3_2_94_2","first-page":"7120753","article-title":"An intrabody drug (rAAV6-INT41) reduces the binding of N-terminal Huntingtin fragment(s) to DNA to basal levels in PC12 cells and delays cognitive loss in the R6\/2 animal model","volume":"2016","author":"Amaro IA","year":"2016","unstructured":"Amaro IA, Henderson LA. An intrabody drug (rAAV6-INT41) reduces the binding of N-terminal Huntingtin fragment(s) to DNA to basal levels in PC12 cells and delays cognitive loss in the R6\/2 animal model. J Neurodegener Dis 2016; 2016: 7120753.","journal-title":"J Neurodegener Dis"},{"key":"e_1_3_2_95_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200710158"},{"key":"e_1_3_2_96_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2004.07.054"},{"key":"e_1_3_2_97_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408134101"},{"key":"e_1_3_2_98_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4286-09.2009"},{"key":"e_1_3_2_99_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzu041"},{"key":"e_1_3_2_100_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016676"},{"key":"e_1_3_2_101_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzq022"},{"key":"e_1_3_2_102_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-021-00332-6"},{"key":"e_1_3_2_103_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-014-1971-6"},{"key":"e_1_3_2_104_2","first-page":"2026.04.09.7169","article-title":"Development of a novel VHH intrabody targeting the N17 region of huntingtin exon 1 protein that prevents inclusion body formation","author":"Wavreil FDM","year":"2026","unstructured":"Wavreil FDM, et al. Development of a novel VHH intrabody targeting the N17 region of huntingtin exon 1 protein that prevents inclusion body formation. bioRxiv 2026: 2026.04.09.716913.","journal-title":"bioRxiv"},{"key":"e_1_3_2_105_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.12.013"},{"key":"e_1_3_2_106_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.101496"},{"key":"e_1_3_2_107_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.105585"},{"key":"e_1_3_2_108_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26684-z"},{"key":"e_1_3_2_109_2","article-title":"A specific Mini-intrabody mediates lysosome degradation of mutant Huntingtin","volume":"10","author":"Li C","year":"2023","unstructured":"Li C, et al. A specific Mini-intrabody mediates lysosome degradation of mutant Huntingtin. Adv Sci (Weinh) 2023; 10: e2301120.","journal-title":"Adv Sci (Weinh)"}],"container-title":["Journal of Huntington's Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/18796397261494078","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/18796397261494078","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/18796397261494078","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T18:49:11Z","timestamp":1791830951000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/18796397261494078"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":108,"alternative-id":["10.1177\/18796397261494078"],"URL":"https:\/\/doi.org\/10.1177\/18796397261494078","relation":{},"ISSN":["1879-6397","1879-6400"],"issn-type":[{"value":"1879-6397","type":"print"},{"value":"1879-6400","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"article-number":"18796397261494078"}}