{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:08:48Z","timestamp":1790770128706,"version":"4.1.0"},"reference-count":129,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T00:00:00Z","timestamp":1638748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministero dell'Universit\u00e0 e della Ricerca","award":["FISR2019_03796"],"award-info":[{"award-number":["FISR2019_03796"]}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PRIN 2017"],"award-info":[{"award-number":["PRIN 2017"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CNCCS","award":["B56G15001140005"],"award-info":[{"award-number":["B56G15001140005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Huntington Disease (HD) is a dominant, lethal neurodegenerative disorder caused by the abnormal expansion (&gt;35 copies) of a CAG triplet located in exon 1 of the HTT gene encoding the huntingtin protein (Htt). Mutated Htt (mHtt) easily aggregates, thereby inducing ER stress that in turn leads to neuronal injury and apoptosis. Therefore, both the inhibition of mHtt aggregate formation and the acceleration of mHtt degradation represent attractive strategies to delay HD progression, and even for HD treatment. Here, we describe the mechanism underlying mHtt degradation by the ubiquitin\u2013proteasome system (UPS), which has been shown to play a more important role than the autophagy\u2013lysosomal pathway. In particular, we focus on E3 ligase proteins involved in the UPS and detail their structure\u2013function relationships. In this framework, we discuss the possible exploitation of PROteolysis TArgeting Chimeras (PROTACs) for HD therapy. PROTACs are heterobifunctional small molecules that comprise two different ligands joined by an appropriate linker; one of the ligands is specific for a selected E3 ubiquitin ligase, the other ligand is able to recruit a target protein of interest, in this case mHtt. As a consequence of PROTAC binding, mHtt and the E3 ubiquitin ligase can be brought to a relative position that allows mHtt to be ubiquitinated and, ultimately, allows a reduction in the amount of mHtt in the cell.<\/jats:p>","DOI":"10.3390\/jpm11121309","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T22:18:42Z","timestamp":1638829122000},"page":"1309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Huntingtin Ubiquitination Mechanisms and Novel Possible Therapies to Decrease the Toxic Effects of Mutated Huntingtin"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8966-8554","authenticated-orcid":false,"given":"Annarita","family":"Fiorillo","sequence":"first","affiliation":[{"name":"Department of Biochemical Sciences \u201cA. Rossi Fanelli\u201d, \u201cSapienza\u201d University of Rome, P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2566-3049","authenticated-orcid":false,"given":"Veronica","family":"Morea","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Pathology of The National Research Council of Italy (CNR), P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9913-0635","authenticated-orcid":false,"given":"Gianni","family":"Colotti","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Pathology of The National Research Council of Italy (CNR), P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7754-399X","authenticated-orcid":false,"given":"Andrea","family":"Ilari","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Pathology of The National Research Council of Italy (CNR), P.le A. Moro 5, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/mds.25717","article-title":"Multisource ascertainment of Huntington disease in Canada: Prevalence and population at risk","volume":"29","author":"Fisher","year":"2013","journal-title":"Mov. Disord."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/B978-0-12-801893-4.00003-1","article-title":"Epidemiology of Huntington disease","volume":"144","author":"Kay","year":"2017","journal-title":"Handb. Clin. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1159\/000516767","article-title":"Modeling Manifest Huntington\u2019s Disease Prevalence Using Di-agnosed Incidence and Survival Time","volume":"55","author":"Crowell","year":"2021","journal-title":"Neuroepidemiology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1016\/j.bbadis.2016.08.019","article-title":"An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington\u2019s disease related cardiomyopathy","volume":"1862","author":"Toczek","year":"2016","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3389\/fphys.2017.00127","article-title":"Transcriptional Signature of an Altered Purine Metabolism in the Skeletal Muscle of a Huntington\u2019s Disease Mouse Model","volume":"8","author":"Mielcarek","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1058464","DOI":"10.1080\/21675511.2015.1058464","article-title":"Huntington\u2019s disease is a multi-system disorder","volume":"3","author":"Mielcarek","year":"2015","journal-title":"Rare Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1056\/NEJM199405193302001","article-title":"A Worldwide Study of the Huntington\u2019s Disease Mutation: The Sensitivity and Specificity of Measuring CAG Repeats","volume":"330","author":"Kremer","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.1523\/JNEUROSCI.19-07-02522.1999","article-title":"Nuclear and Neuropil Aggregates in Huntington\u2019s Disease: Relationship to Neuropathology","volume":"19","author":"Gutekunst","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Quarrell, O., O\u2019Donovan, K.L., Bandmann, O., and Strong, M. (2012). The Prevalence of Juvenile Huntington\u2019s Disease: A Review of the Lit-erature and Meta-Analysis. PLoS Curr., 4.","DOI":"10.1371\/4f8606b742ef3"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/S1474-4422(18)30294-1","article-title":"Biological and clinical manifestations of juvenile Huntington\u2019s disease: A retrospective analysis","volume":"17","author":"Fusilli","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13285","DOI":"10.1523\/JNEUROSCI.4393-08.2008","article-title":"Differential Activities of the Ubiquitin-Proteasome System in Neurons versus Glia May Account for the Preferential Accumulation of Misfolded Proteins in Neurons","volume":"28","author":"Tydlacka","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"663","DOI":"10.4161\/auto.6.5.12336","article-title":"Clearance of mutant huntingtin","volume":"6","author":"Li","year":"2010","journal-title":"Autophagy"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1093\/hmg\/ddq127","article-title":"Inhibiting the ubiquitin\u2013proteasome system leads to preferential accumulation of toxic N-terminal mutant huntingtin fragments","volume":"19","author":"Li","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1146\/annurev-pharmtox-010814-124332","article-title":"Targeting Proteostasis Through the Protein Quality Control Function of the Hsp90\/Hsp70-based Chaperone Machinery for Treatment of Adult Onset Neurodegenerative Diseases","volume":"55","author":"Pratt","year":"2015","journal-title":"Annu. Rev. Pharm. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"254","DOI":"10.3389\/fnins.2017.00254","article-title":"The Hsp70\/Hsp90 Chaperone Machinery in Neurodegenerative Diseases","volume":"11","author":"Lackie","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/nature25502","article-title":"Europe PMC Funders Group The cryo-electron microscopy structure of huntingtin","volume":"555","author":"Guo","year":"2018","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Qi, L., Zhang, X.D., Wu, J.C., Lin, F., Wang, J., DiFiglia, M., and Qin, Z.H. (2012). The Role of Chaperone-Mediated Autophagy in Huntingtin Deg-radation. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046834"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1074\/jbc.M111.294801","article-title":"A Screen for Enhancers of Clearance Identifies Huntingtin as a Heat Shock Protein 90 (Hsp90) Client Protein","volume":"287","author":"Baldo","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1146\/annurev.biochem.67.1.425","article-title":"The ubiquitin system","volume":"67","author":"Hershko","year":"1998","journal-title":"Annu. Rev. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/S0021-9258(18)34957-3","article-title":"\"Covalent affinity\" purification of ubiquitin-activating enzyme","volume":"257","author":"Ciechanover","year":"1982","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/0006-291X(85)91050-2","article-title":"Occurrence of a polyubiquitin structure in ubiquitin-protein conjugates","volume":"128","author":"Hershko","year":"1985","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1146\/annurev-biochem-060310-170328","article-title":"The ubiquitin code","volume":"81","author":"Komander","year":"2012","journal-title":"Annu. Rev. Biochem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/nature11722","article-title":"Ubiquitin chain conformation regulates recog-nition and activity of interacting proteins","volume":"492","author":"Ye","year":"2012","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/cr.2016.39","article-title":"Ubiquitin modifications","volume":"26","author":"Swatek","year":"2016","journal-title":"Cell Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.celrep.2015.06.061","article-title":"The Proteasome Distinguishes between Heterotypic and Homotypic Lysine-11-Linked Polyubiquitin Chains","volume":"12","author":"Grice","year":"2015","journal-title":"Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Dougherty, S.E., Maduka, A.O., Inada, T., and Silva, G.M. (2020). Expanding Role of Ubiquitin in Translational Control. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21031151"},{"key":"ref_28","first-page":"125","article-title":"The emerging complexity of ubiquitin architecture","volume":"161","author":"Ohtake","year":"2017","journal-title":"J. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/nsmb.1873","article-title":"Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne","volume":"17","author":"Bremm","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4198","DOI":"10.1038\/emboj.2010.300","article-title":"c-IAP1 and UbcH5 promote K11-linked polyubiquitination of RIP1 in TNF signalling","volume":"29","author":"Dynek","year":"2010","journal-title":"EMBO J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4325","DOI":"10.1091\/mbc.E15-02-0102","article-title":"Effcient APC\/C substrate degradation in cells undergoing mitotic exit depends on K11 ubiquitin linkages","volume":"26","author":"Min","year":"2015","journal-title":"Mol. Biol. Cell"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Saito, K., Horikawa, W., and Ito, K. (2015). Inhibiting K63 Polyubiquitination Abolishes No-Go Type Stalled Translation Surveillance in Saccharomyces cerevisiae. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005197"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/nsmb.2955","article-title":"K63 polyubiquitination is a new modulator of the oxidative stress response","volume":"22","author":"Silva","year":"2015","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"18337","DOI":"10.1074\/jbc.RA118.003975","article-title":"Crystal structure of a human ubiquitin E1-ubiquitin complex reveals con-served functional elements essential for activity","volume":"293","author":"Lv","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1038\/cr.2016.35","article-title":"E2 enzymes: More than just middle men","volume":"26","author":"Stewart","year":"2016","journal-title":"Cell Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3389\/fgene.2018.00029","article-title":"A Comprehensive Atlas of E3 Ubiquitin Ligase Mutations in Neurological Disorders","volume":"9","author":"George","year":"2018","journal-title":"Front. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1152\/physiolgenomics.00031.2016","article-title":"Comprehensive database of human E3 ubiquitin ligases: Appli-cation to aquaporin-2 regulation","volume":"48","author":"Medvar","year":"2016","journal-title":"Physiol. Genom."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/nrm2690","article-title":"Physiological functions of the HECT family of ubiquitin ligases","volume":"10","author":"Rotin","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1242\/jcs.091777","article-title":"HECT and RING finger families of E3 ubiquitin ligases at a glance","volume":"125","author":"Metzger","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1126\/science.286.5443.1321","article-title":"Structure of an E6AP-UbcH7 complex: Insights into ubiquitination by the E2-E3 enzyme cascade","volume":"286","author":"Huang","year":"1999","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1016\/j.molcel.2009.11.010","article-title":"Insights into Ubiquitin Transfer Cascades from a Structure of a UbcH5B\u223cUbiquitin-HECTNEDD4L Complex","volume":"36","author":"Kamadurai","year":"2009","journal-title":"Mol. Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/S0092-8674(00)00057-X","article-title":"Structure of a c-Cbl-UbcH7 complex: RING domain function in ubiquitin-protein ligases","volume":"102","author":"Zheng","year":"2000","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/S0006-291X(03)00245-6","article-title":"U-box proteins as a new family of ubiquitin ligases","volume":"302","author":"Hatakeyama","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1146\/annurev-biochem-062917-011931","article-title":"Structure and Function of the 26S Proteasome","volume":"87","author":"Bard","year":"2018","journal-title":"Annu. Rev. Biochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41586-018-0736-4","article-title":"Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome","volume":"565","author":"Dong","year":"2018","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/00005072-198511000-00003","article-title":"Neuropathological classification of Huntington\u2019s disease","volume":"44","author":"Vonsattel","year":"1985","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_47","first-page":"65","article-title":"The biological function of the Huntingtin protein and its relevance to Huntington\u2019s Disease pathology","volume":"5","author":"Schulte","year":"2011","journal-title":"Curr. Trends Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1515\/bmc-2015-0001","article-title":"The emerging role of the first 17 amino acids of huntingtin in Huntington\u2019s disease","volume":"6","author":"Arndt","year":"2015","journal-title":"Biomol. Concepts"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1038\/nn1702","article-title":"Palmitoylation of huntingtin by HIP14is essential for its trafficking and function","volume":"9","author":"Yanai","year":"2006","journal-title":"Nat. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Seefelder, M., Alva, V., Huang, B., Engler, T., Baumeister, W., Guo, Q., Fernandez-Busnadiego, R., Lupas, A.N., and Kochanek, S. (2020). The evolution of the huntingtin-associated protein 40 (HAP40) in conjunction with huntingtin. BMC Evol. Biol., 20.","DOI":"10.1186\/s12862-020-01705-5"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1016\/j.str.2021.04.003","article-title":"Pathological polyQ expansion does not alter the con-formation of the Huntingtin-HAP40 complex","volume":"29","author":"Huang","year":"2021","journal-title":"Structure"},{"key":"ref_52","first-page":"262","article-title":"Huntingtin functions as a scaffold for selective macroautophagy","volume":"17","author":"Rui","year":"2015","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10045","DOI":"10.1073\/pnas.0610628104","article-title":"Huntingtin facilitates dynein\/dynactin-mediated vesicle transport","volume":"104","author":"Caviston","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.cell.2004.06.018","article-title":"Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules","volume":"118","author":"Gauthier","year":"2004","journal-title":"Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.neuron.2010.06.027","article-title":"Huntingtin Is Required for Mitotic Spindle Orientation and Mammalian Neurogenesis","volume":"67","author":"Godin","year":"2010","journal-title":"Neuron"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/ng1095-155","article-title":"Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington\u2019s disease gene homologue","volume":"11","author":"Zeitlin","year":"1995","journal-title":"Nat. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9455","DOI":"10.1523\/JNEUROSCI.4699-13.2014","article-title":"Huntingtin Is Required for Normal Excitatory Synapse Development in Cortical and Striatal Circuits","volume":"34","author":"McKinstry","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/81593","article-title":"Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice","volume":"26","author":"Dragatsis","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1523\/JNEUROSCI.2443-18.2018","article-title":"Loss-of-Huntingtin in Medial and Lateral Ganglionic Lineages Differentially Disrupts Regional Interneuron and Projection Neuron Subtypes and Promotes Huntington\u2019s Disease-Associated Behavioral, Cellular, and Pathological Hallmarks","volume":"39","author":"Mehler","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1007\/s00726-017-2417-2","article-title":"Glucose transportation in the brain and its impairment in Huntington disease: One more shade of the energetic metabolism failure?","volume":"49","author":"Morea","year":"2017","journal-title":"Amino Acids"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Tomczyk, M., Glaser, T., Ulrich, H., Slominska, E.M., and Smolenski, R.T. (2020). Huntingtin protein maintains balanced energetics in mouse cardiomyocytes. Nucleosides Nucleotides Nucleic Acids, 1\u20138.","DOI":"10.1080\/15257770.2020.1815769"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.ydbio.2014.04.005","article-title":"Huntingtin protein is essential for mitochondrial metab-olism, bioenergetics and structure in murine embryonic stem cells","volume":"391","author":"Ismailoglu","year":"2014","journal-title":"Dev. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1111\/j.1471-4159.2005.03605.x","article-title":"Wild-type huntingtin protects neurons from excitotoxicity","volume":"96","author":"Leavitt","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.celrep.2019.12.069","article-title":"Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival","volume":"30","author":"Burrus","year":"2020","journal-title":"Cell Rep."},{"key":"ref_65","first-page":"1","article-title":"Wild-type huntingtin regulates human macrophage function","volume":"10","author":"Farag","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1126\/science.1092194","article-title":"SUMO Modification of Huntingtin and Hun-tington\u2019s Disease Pathology","volume":"304","author":"Steffan","year":"2004","journal-title":"Science"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1074\/mcp.O112.027094","article-title":"Refined preparation and use of anti-diglycine remnant (K-\u03b5-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments","volume":"12","author":"Udeshi","year":"2013","journal-title":"Mol. Cell Proteom."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/s41594-018-0084-y","article-title":"UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites","volume":"25","author":"Akimov","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1002\/pmic.201100380","article-title":"Mass spectrometric identification of novel posttranslational modifi-cation sites in Huntingtin","volume":"12","author":"Dong","year":"2012","journal-title":"Proteomics"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1038\/nmeth.2518","article-title":"Integrated proteomic analysis of post-translational mod-ifications by serial enrichment","volume":"10","author":"Mertins","year":"2013","journal-title":"Nat. Methods"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"M111.013284","DOI":"10.1074\/mcp.M111.013284","article-title":"A proteome-wide, quantitative survey of in vivo ubiq-uitylation sites reveals widespread regulatory roles","volume":"10","author":"Wagner","year":"2011","journal-title":"Mol. Cell Proteom."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1016\/j.celrep.2016.04.047","article-title":"Multiomic Analysis of the UV-Induced DNA Damage Response","volume":"15","author":"Boeing","year":"2016","journal-title":"Cell Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1038\/ncb2579","article-title":"Systems-wide analysis of ubiquitylation dy-namics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass","volume":"14","author":"Povlsen","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"19385","DOI":"10.1074\/jbc.271.32.19385","article-title":"Huntingtin Is Ubiquitinated and Interacts with a Specific Ubiquitin-conjugating Enzyme","volume":"271","author":"Kalchman","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1126\/science.1172871","article-title":"Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity","volume":"324","author":"Subramaniam","year":"2009","journal-title":"Science"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1002\/(SICI)1097-4547(19990915)57:6<782::AID-JNR3>3.0.CO;2-9","article-title":"Rhes: A striatal-specific Ras homolog related to Dexras","volume":"57","author":"Falk","year":"1999","journal-title":"J. Neurosci. Res."},{"key":"ref_77","first-page":"2223","article-title":"Bioinformatics analysis of Ras homologue enriched in the striatum, a potential target for Huntington\u2019s disease therapy","volume":"44","author":"Carbo","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.nbd.2017.10.002","article-title":"The ubiquitin conjugating enzyme Ube2W regulates solubility of the Huntington\u2019s disease protein, huntingtin","volume":"109","author":"Wang","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.mcn.2006.09.006","article-title":"Ubiquitin-conjugating enzyme E2-25K increases aggregate formation and cell death in polyglutamine diseases","volume":"34","author":"Fischer","year":"2007","journal-title":"Mol. Cell Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6235","DOI":"10.1093\/hmg\/ddu343","article-title":"Deficiency of Ube3a in Huntington\u2019s disease mice brain increases aggregate load and accelerates disease pathology","volume":"23","author":"Maheshwari","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"7648","DOI":"10.1074\/jbc.M706620200","article-title":"E6-AP Promotes Misfolded Polyglutamine Proteins for Proteasomal Degradation and Suppresses Polyglutamine Protein Aggregation and Toxicity","volume":"283","author":"Mishra","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"93","DOI":"10.3389\/fnmol.2016.00093","article-title":"A decade of boon or burden: What has the chip ever done for cellular protein quality control mechanism implicated in neurodegeneration and aging?","volume":"9","author":"Joshi","year":"2016","journal-title":"Front. Mol. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.yexcr.2006.10.031","article-title":"Ubiquitin ligase Hrd1 enhances the degradation and sup-presses the toxicity of polyglutamine-expanded huntingtin","volume":"313","author":"Yang","year":"2007","journal-title":"Exp. Cell Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.brainres.2009.05.039","article-title":"Effects of partial suppression of parkin on huntingtin mutant R6\/1 mice","volume":"1281","author":"Rubio","year":"2009","journal-title":"Brain Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e428","DOI":"10.1038\/cddis.2012.166","article-title":"Dysregulation of core components of SCF complex in poly-glutamine disorders","volume":"3","author":"Bhutani","year":"2012","journal-title":"Cell Death Dis."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3032","DOI":"10.1073\/pnas.1314421111","article-title":"HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response","volume":"111","author":"Rotblat","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.brainres.2016.03.027","article-title":"Atypical ubiquitination by E3 ligase WWP1 inhibits the proteasome-mediated deg-radation of mutant huntingtin","volume":"1643","author":"Lin","year":"2016","journal-title":"Brain Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"25108","DOI":"10.1074\/jbc.M110.187591","article-title":"Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) Associates with Huntingtin Protein and Promotes Its Atypical Ubiquitination to Enhance Aggregate Formation","volume":"286","author":"Zucchelli","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/aps.2018.11","article-title":"Proteostasis in Huntington\u2019s disease: Disease mechanisms and therapeutic opportunities","volume":"39","author":"Harding","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.nbd.2015.05.010","article-title":"The deubiquitinase ataxin-3 requires Rad23 and DnaJ-1 for its neuroprotective role in Drosophila melanogaster","volume":"82","author":"Tsou","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"14797","DOI":"10.1038\/s41598-017-13711-7","article-title":"HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP","volume":"7","author":"He","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.molcel.2003.08.005","article-title":"Essential role of E2-25K\/Hip-2 in mediating amyloid-beta neu-rotoxicity","volume":"12","author":"Song","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1093\/hmg\/ddm311","article-title":"Soluble polyglutamine oligomers formed prior to in-clusion body formation are cytotoxic","volume":"17","author":"Takahashi","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1002\/pro.3832","article-title":"Crystal structure of the catalytic C-lobe of the HECT-type ubiquitin ligase E6AP","volume":"29","author":"Ries","year":"2020","journal-title":"Protein Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"5706","DOI":"10.1073\/pnas.1402215111","article-title":"Differential ubiquitination and degradation of huntingtin fragments modulated by ubiquitin-protein ligase E3A","volume":"111","author":"Bhat","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_96","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":"ref_97","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1038\/ncomms2982","article-title":"Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases","volume":"4","author":"Lougheed","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0074-7696(04)38003-4","article-title":"The Centrosome in Higher Organisms: Structure, Composition, and Duplication","volume":"238","author":"Ou","year":"2004","journal-title":"Int. Rev. Cytol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/416703a","article-title":"Structure of the Cul1\u2013Rbx1\u2013Skp1\u2013F box Skp2 SCF ubiquitin ligase complex","volume":"416","author":"Zheng","year":"2002","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1042\/BJ20141282","article-title":"Regulation of the human ether-a-go-go-related gene (hERG) potassium channel by Nedd4 family interacting proteins (Ndfips)","volume":"472","author":"Kang","year":"2015","journal-title":"Biochem. J."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"19132","DOI":"10.1074\/jbc.M116.722637","article-title":"Ubiquitin-specific protease 36 (USP36) controls neuronal precursor cell-expressed developmentally down-regulated 4-2 (Nedd4-2) actions over the neu-rotrophin receptor TrkA and potassium voltage-gated channels 7.2\/3 (kv7.2\/3)","volume":"291","author":"Anta","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0092-8674(00)00126-4","article-title":"Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain","volume":"103","author":"Deng","year":"2000","journal-title":"Cell"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"4102","DOI":"10.1074\/jbc.M609503200","article-title":"Site-specific Lys-63-linked tumor necrosis factor recep-tor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation","volume":"282","author":"Lamothe","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1073\/pnas.1721788115","article-title":"Mechanism of ubiquitin transfer promoted by TRAF","volume":"115","author":"Fu","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/embor.2008.93","article-title":"Atypical ubiquitin chains: New molecular signals. \u201cProtein Modifications: Beyond the Usual Suspects\u201d Review Series","volume":"9","author":"Ikeda","year":"2008","journal-title":"EMBO Rep."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1126\/science.aab1433","article-title":"Phthalimide conjugation as a strategy for in vivo target protein degradation","volume":"348","author":"Winter","year":"2015","journal-title":"Science"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1021\/acschembio.5b00216","article-title":"Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD","volume":"10","author":"Zengerle","year":"2015","journal-title":"ACS Chem. Biol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.bmcl.2018.01.012","article-title":"Degradation of huntingtin mediated by a hybrid molecule composed of IAP antagonist linked to phenyldiazenyl benzothiazole derivative","volume":"28","author":"Tomoshige","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"5820","DOI":"10.1021\/ja100691p","article-title":"Protein Knockdown Using Methyl Bestatin\u2212Ligand Hybrid Molecules: Design and Synthesis of Inducers of Ubiquitination-Mediated Degradation of Cellular Retinoic Acid-Binding Proteins","volume":"132","author":"Itoh","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1038\/nature00767","article-title":"Structural basis for the recognition of hydrox-yproline in HIF-1\u03b1 by pVHL","volume":"417","author":"Hon","year":"2002","journal-title":"Nature"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1126\/science.1073440","article-title":"Structure of an HIF-1\u03b1-pVHL complex: Hydroxyproline recognition in signaling","volume":"296","author":"Min","year":"2002","journal-title":"Science"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3748","DOI":"10.1021\/ja039025z","article-title":"Chemical Genetic Control of Protein Levels: Selective in Vivo Targeted Degradation","volume":"126","author":"Schneekloth","year":"2004","journal-title":"J. Am. Chem. Soc."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"8657","DOI":"10.1021\/jm5011258","article-title":"Structure-Guided Design and Optimization of Small Molecules Targeting the Protein\u2013Protein Interaction between the von Hippel\u2013Lindau (VHL) E3 Ubiquitin Ligase and the Hypoxia Inducible Factor (HIF) Alpha Subunit with in Vitro Nanomolar Affinities","volume":"57","author":"Galdeano","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/nature05175","article-title":"Molecular architecture and assembly of the DDB1\u2013CUL4A ubiquitin ligase machinery","volume":"443","author":"Angers","year":"2006","journal-title":"Nature"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nature13527","article-title":"Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide","volume":"512","author":"Fischer","year":"2014","journal-title":"Nature"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/nsmb.2874","article-title":"Structure of the human Cere-blon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs","volume":"21","author":"Chamberlain","year":"2014","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.chembiol.2015.05.009","article-title":"Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD","volume":"22","author":"Lu","year":"2015","journal-title":"Chem. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"3500","DOI":"10.1200\/JCO.2020.38.15_suppl.3500","article-title":"First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and\/or abiraterone (ABI)","volume":"38","author":"Petrylak","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"P5-04-18","DOI":"10.1158\/1538-7445.SABCS18-P5-04-18","article-title":"Abstract P5-04-18: ARV-471, an oral estrogen receptor PROTAC degrader for breast cancer","volume":"79","author":"Flanagan","year":"2019","journal-title":"Cancer Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/j.febslet.2011.03.019","article-title":"Specific degradation of CRABP-II via cIAP1-mediated ubiquitylation induced by hybrid molecules that crosslink cIAP1 and the target protein","volume":"585","author":"Okuhira","year":"2011","journal-title":"FEBS Lett."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1007\/s00044-020-02539-y","article-title":"Nrf2 activation through the inhibition of Keap1\u2013Nrf2 protein\u2013protein interaction","volume":"29","author":"Lee","year":"2020","journal-title":"Med. Chem. Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.ejmech.2018.01.063","article-title":"Discovery of a Keap1-dependent peptide PROTAC to knockdown Tau by ubiq-uitination-proteasome degradation pathway","volume":"146","author":"Lu","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-72491-9","article-title":"Bardoxolone conjugation enables targeted protein deg-radation of BRD","volume":"10","author":"Tong","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2822","DOI":"10.1021\/acschembio.9b00704","article-title":"Development of Small Molecule Chimeras That Recruit AhR E3 Ligase to Target Proteins","volume":"14","author":"Ohoka","year":"2019","journal-title":"ACS Chem. Biol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1021\/acschembio.8b01083","article-title":"Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications","volume":"14","author":"Ward","year":"2019","journal-title":"ACS Chem. Biol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/s41589-019-0304-8","article-title":"Harnessing the anti-cancer natural product nimbolide for targeted protein degradation","volume":"15","author":"Spradlin","year":"2019","journal-title":"Nat. Chem. Biol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"11530","DOI":"10.1002\/anie.201706529","article-title":"Discovery of Small Molecules that Induce the Degradation of Huntingtin","volume":"56","author":"Tomoshige","year":"2017","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"115175","DOI":"10.1016\/j.bmc.2019.115175","article-title":"Application of protein knockdown strategy targeting \u03b2-sheet structure to multiple disease-associated polyglutamine proteins","volume":"28","author":"Yamashita","year":"2019","journal-title":"Bioorg. Med. Chem."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-019-1722-1","article-title":"Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds","volume":"575","author":"Li","year":"2019","journal-title":"Nature"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/12\/1309\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:40:12Z","timestamp":1760168412000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/12\/1309"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,6]]},"references-count":129,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["jpm11121309"],"URL":"https:\/\/doi.org\/10.3390\/jpm11121309","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,6]]}}}