Volume 10 Number 2 2026
Ubiquitin-Proteasome Dysfunction in Huntington's Disease and Its Mechanistic Insights and Druggable Targets Across the Proteostasis Network
Fayez Mohammed Hubayni Almutairi 1, Fahad Suliman A Alsaif 1, Saad Abdulrazaq Ahmed Hayjan 1, Mohammed Ahmed Almansour 1, Rana Nashmi Alanazi 1, Khawla Mohammed Abdullah Al-Naim 2*
Integrative Biomedical Research 10 (2) 1-8 https://doi.org/10.25163/biomedical.10210928
Submitted: 25 September 2026 Revised: 17 November 2026 Accepted: 26 November 2026 Published: 28 November 2026
Huntington's disease (HD) offers a particularly instructive, if sobering, window into what happens when a cell's protein-clearance machinery is asked to do more than it can bear. Background: the ubiquitin-proteasome system (UPS) is the principal route by which short-lived and misfolded proteins are removed from eukaryotic cells, and it becomes especially indispensable in the neuronal nucleus, which has no meaningful autophagic backup. In HD, an expanded polyglutamine tract within mutant huntingtin (mHTT) appears to overwhelm this system through several compounding routes rather than any single lesion. Methods: we synthesized findings from 37 primary and review sources addressing UPS biology, HD pathogenesis, and emerging degrader technologies, following a structured, reproducible literature-identification and thematic-extraction protocol comparable to a rapid systematic review. Sources were screened for relevance to proteasome structure and function, E3 ligase/deubiquitinase (DUB) biology in HD, post-translational modification (PTM) crosstalk, and targeted protein degradation (TPD). Results: the synthesis converges on a picture in which soluble mHTT oligomers allosterically lock the 20S proteasome gate, aggregation-prone fragments stall within the catalytic chamber, and ubiquitin itself becomes a limiting resource ("ubiquitin stress"). These defects are not uniform across the cell; the nucleus, the synapse (via the Ube3a-Arc-AMPA axis), and the outer mitochondrial membrane each fail through distinct, druggable mechanisms. Opposing E3 ligases (CHIP, TRIM37, WWP1) and a competitive tug-of-war between ubiquitination and SUMOylation further shape whether mHTT is cleared or stabilized. Conclusion: targeted protein degradation platforms, DUB inhibitors, and proteasome activators together sketch a plausible, if still preclinical, path toward restoring proteostasis in HD and related proteinopathies.
Keywords: Huntington's disease; ubiquitin-proteasome system; huntingtin; E3 ubiquitin ligase; deubiquitinase; SUMOylation; targeted protein degradation
Aladdin, A., Király, R., Boto, P., Regdon, Z., & Tar, K. (2019). Juvenile huntington's disease skin fibroblasts respond with elevated parkin level and increased proteasome activity as a potential mechanism to counterbalance the pathological stress. International Journal of Molecular Sciences, 20(21), 5338. https://doi.org/10.3390/ijms20215338
Alexopoulou, Z., Lang, J., Perrett, R. M., Elschami, M., Hurry, M. E. D., Kim, H. T., ... & Youle, R. J. (2016). Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease. Proceedings of the National Academy of Sciences, 113(32), E4688-E4697. https://doi.org/10.1073/pnas.1523597113
Amm, I., Sommer, T., & Wolf, D. H. (2014). Protein quality control and elimination of misfolded proteins by the ubiquitin-proteasome system in the different cellular compartments of eukaryotic cells. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1843(1), 182-196. https://doi.org/10.1016/j.bbamcr.2013.06.031
Argueti-Ostrovsky, S., Alfahel, L., Kahn, J., & Israelson, A. (2021). All roads lead to Rome: Different molecular players converge to common toxic pathways in neurodegeneration. Cells, 10(9), 2438. https://doi.org/10.3390/cells10092438
Bennett, E. J., Shaler, T. A., Woodman, B., Ryu, K. Y., Zaitseva, T. S., Becker, C. H., Bates, G. P., Schulman, H., & Kopito, R. R. (2007). Global changes to the ubiquitin system in Huntington's disease. Nature, 448(7154), 704-708. https://doi.org/10.1038/nature06022
Cervantes-Arriaga, A., Beltrán-Torres, A. X., Romero-García, D., & Rodríguez-Violante, M. (2026). Huntington's disease in the era of somatic instability, biomarkers, and targeted therapies: A narrative review. Revista de Investigación Clínica, 78(3), 100047. https://doi.org/10.1016/j.ric.2026.100047
Chan, S. C., Tung, C. W., Chang, C. Y., Su, C. C., Chen, Y. C., Wu, P. M., Tung, C. Y., Chen, S. F., Chen, C. Y., Kuo, H. Y., Cheng, P. H., Chen, C. M., & Yang, S. H. (2026). Wild-type C9orf72 drives proteasomal dysfunction and mutant aggregates via a Stat1-Isg15 axis in Huntington's disease. Neurotherapeutics, 23(3), e00970. https://doi.org/10.1016/j.neurot.2026.e00970
Ciechanover, A., & Brundin, P. (2003). The ubiquitin-proteasome system in neurodegenerative diseases: Sometimes the chicken, sometimes the egg. Neuron, 40(2), 427-446. https://doi.org/10.1016/S0896-6273(03)00606-8
Dai, Y., Wang, H., Zhao, A., Li, J., Zhao, G., Hu, S., & Li, B. (2023). A comprehensive perspective of Huntington's disease and mitochondrial dysfunction. Mitochondrion, 70, 8-19. https://doi.org/10.1016/j.mito.2023.03.001
Fang, T. S. Z., Sun, Y., Pearce, A. C., Eleuteri, S., Kemp, M., Luckhurst, C. A., ... & Youle, R. J. (2023). Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson's disease mouse model. Nature Communications, 14, 7295. https://doi.org/10.1038/s41467-023-42876-1
Ferreira, S., Menezes, R., Trougakos, I. P., Gumeni, S., Bolaños-Garcia, V. M., Santos, C. N. D., & Ávila-Gálvez, M. Á. (2026). The amazing ubiquitin-proteasome system: Structural components and implication in aging and neurodegenerative diseases. Journal of Nutritional Biochemistry, 147, 110127. https://doi.org/10.1016/j.jnutbio.2025.110127
Gadade, D. D., Chauhan, N. S., Modi, A., Kumar, V., Shah, K., Jain, N., Sareen, R., & Gadade, D. D. (2024). Natural bioactives that exhibit therapeutic potential against Huntington's disease. Brain, Behavior, and Immunity - Integrative, 8, 100091. https://doi.org/10.1016/j.bbii.2024.100091
Ge, P., Dawson, V. L., & Dawson, T. M. (2020). PINK1 and Parkin mitochondrial quality control: A source of regional vulnerability in Parkinson's disease. Molecular Neurodegeneration, 15(1), 20. https://doi.org/10.1186/s13024-020-00367-w
Guo, X., & Qi, X. (2017). Valosin-containing protein and mitochondria-associated protein degradation in Huntington's disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1863(2), 552-559. https://doi.org/10.1016/j.bbadis.2016.11.020
He, W. T., Xue, W., Gao, Y. G., Hong, J. Y., Yue, H. W., Jiang, L. L., ... & Hu, H. Y. (2017). HSP90 recognizes the N-terminus of huntingtin involved in regulation of huntingtin aggregation by USP19. Scientific Reports, 7(1), 14797. https://doi.org/10.1038/s41598-017-13711-7
He, W. T., Zheng, X. M., Zhang, Y. H., Gao, Y. G., Song, A. X., van der Goot, F. G., ... & Hu, H. Y. (2016). Cytoplasmic ubiquitin-specific protease 19 (USP19) modulates aggregation of polyglutamine-expanded ataxin-3 and huntingtin through the HSP90 chaperone. PLoS ONE, 11(1), e0147515. https://doi.org/10.1371/journal.pone.0147515
Hou, D. L., Ho, J., Guan, T., Dong, X. X., Zeng, L., Sanders, L. H., Wu, Y. C., Tan, E. K., & Zhou, Z. D. (2026). E3 ubiquitin ligases in neurodegenerative diseases: Pathological mechanisms and therapeutic pipelines. Military Medical Research, 13(1), 100032. https://doi.org/10.1016/j.mmr.2026.100032
Hyun, S., & Shin, D. (2021). Chemical-mediated targeted protein degradation in neurodegenerative diseases. Life, 11(7), 607. https://doi.org/10.3390/life11070607
Iwata, A., Nagashima, Y., Matsumoto, L., Suzuki, T., Yamanaka, T., Date, H., Deoka, K., Nukina, N., & Tsuji, S. (2009). Intranuclear degradation of polyglutamine aggregates by the ubiquitin-proteasome system. Journal of Biological Chemistry, 284(15), 9796-9803. https://doi.org/10.1074/jbc.M808443200
Jana, N. R., & Nukina, N. (2003). Recent advances in understanding the pathogenesis of polyglutamine diseases: Involvement of molecular chaperones and ubiquitin-proteasome pathway. Journal of Chemical Neuroanatomy, 26(2), 95-101. https://doi.org/10.1016/S0891-0618(03)00029-2
Jeon, Y. K., & Kang, Y. K. (2026). Proteasome dysfunction and protein aggregation in neurodegeneration. International Journal of Molecular Sciences, 27(10), 5730. https://doi.org/10.3390/ijms27105730
Johnson, J. T., Awosiminiala, F. W., & Anumudu, C. K. (2025). Exploring protein misfolding and aggregate pathology in neurodegenerative diseases: From molecular mechanisms to clinical interventions. Applied Sciences, 15(18), 10285. https://doi.org/10.3390/app151810285
Joshi, D. C., Chavan, M. B., Gurow, K., Gupta, M., Dhaliwal, J. S., & Ming, L. C. (2025). The role of mitochondrial dysfunction in Huntington's disease: Implications for therapeutic targeting. Biomedicine & Pharmacotherapy, 183, 117827. https://doi.org/10.1016/j.biopha.2025.117827
Kandel, R., Jung, J., & Neal, S. (2024). Proteotoxic stress and the ubiquitin proteasome system. Seminars in Cell and Developmental Biology, 156, 107-120. https://doi.org/10.1016/j.semcdb.2023.08.002
Kim, W., & Seo, H. (2014). Stimulation of GABAergic neurons with the GABAB receptor agonist baclofen enhances ubiquitin-proteasome system function and cell survival in in vitro and in vivo models of Huntington's disease. Biochemical and Biophysical Research Communications, 443(2), 706-711. https://doi.org/10.1016/j.bbrc.2013.12.013
Lazarou, M., Sliter, D. A., Kane, L. A., Sarraf, S. A., Wang, C., Burman, J. L., ... & Youle, R. J. (2015). The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature, 524(7565), 309-314. https://doi.org/10.1038/nature14893
Lee, B.-H., Lee, M. J., Park, S., Oh, D.-C., Elsasser, S., Chen, P.-C., ... & Finley, D. (2010). Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature, 467(7312), 179-184. https://doi.org/10.1038/nature09299
Li, Z., Wang, C., Wang, Z., Zhu, C., Li, J., Sha, T., ... & Lu, B. (2019). Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature, 575(7781), 203-209. https://doi.org/10.1038/s41586-019-1722-1
Lin, L., Jin, Z., Tan, H., Xu, Q., Peng, T., & Li, H. (2016). Atypical ubiquitination by E3 ligase WWP1 inhibits the proteasome-mediated degradation of mutant huntingtin. Brain Research, 1643, 103-112. https://doi.org/10.1016/j.brainres.2016.04.053
Liu, Y., Fallon, L., Lashuel, H. A., Liu, Z., & Lansbury, P. T., Jr. (2002). The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell, 111(2), 209-218. https://doi.org/10.1016/S0092-8674(02)01018-8
Ma, P., Li, Y., Wang, H., & Mao, B. (2021). Haploinsufficiency of the TDP43 ubiquitin E3 ligase RNF220 leads to ALS-like motor neuron defects in the mouse. Journal of Molecular Cell Biology, 13(5), 374-382. https://doi.org/10.1093/jmcb/mjab013
Maheshwari, M., Shekhar, S., Singh, B. K., Jamal, I., Vatsa, N., Kumar, V., ... & Jana, N. R. (2014). Deficiency of Ube3a in Huntington's disease mice brain increases aggregate load and accelerates disease pathology. Human Molecular Genetics, 23(13), 6235-6245. https://doi.org/10.1093/hmg/ddu343
Maheshwari, M., Shekhar, S., Singh, B. K., Jamal, I., Vatsa, N., Kumar, V., Mishra, A., Dikshit, P., Purkayastha, S., Sharma, J., Nukina, N., & Jana, N. R. (2012). Recruitment of Ube3a into mutant huntingtin nuclear aggregates leads to synaptic abnormalities in Huntington's disease mouse model. Journal of Biological Chemistry, 287(22), 19385-19394. https://doi.org/10.1074/jbc.M112.075028
Miller, V. M., Nelson, R. F., Gouvion, C. M., Williams, A., Rodriguez-Lebron, E., Harper, S. Q., ... & Paulson, H. L. (2005). CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. Journal of Neuroscience, 25(39), 9152-9161. https://doi.org/10.1523/JNEUROSCI.3001-05.2005
Mishra, A., Dikshit, P., Purkayastha, S., Sharma, J., Nukina, N., & Jana, N. R. (2008). E6-AP promotes misfolded polyglutamine proteins for proteasomal degradation and suppresses polyglutamine protein aggregation and toxicity. Journal of Biological Chemistry, 283(12), 7648-7656. https://doi.org/10.1074/jbc.M706620200
Myeku, N., Clelland, C. L., Emrani, S., Kukushkin, N. V., Yu, W. H., Goldberg, A. L., & Duff, K. E. (2016). Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nature Medicine, 22(1), 46-53. https://doi.org/10.1038/nm.4011
Ojalvo-Pacheco, J., Yakhine-Diop, S. M. S., Fuentes, J. M., Paredes-Barquero, M., & Niso-Santano, M. (2024). Role of TFEB in Huntington's disease. Biology, 13(4), 238. https://doi.org/10.3390/biology13040238
Ortega-Perez, J., & Lucas, J. J. (2024). Deregulation of autophagic and proteolytic mechanisms in Huntington's disease: Role of lysosome-mediated autophagy and TFEB. Biology, 13, 238. https://doi.org/10.3390/biology13040238
Petrucelli, L., Dickson, D. W., Kehoe, K., Taylor, J., Snyder, H., Grover, A., ... & McGowan, E. (2004). CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Human Molecular Genetics, 13(6), 703-714. https://doi.org/10.1093/hmg/ddh083
Poppek, D., Keck, S., Ermak, G., Jung, T., Stolzing, A., Ullrich, O., ... & Grune, T. (2006). Phosphorylation inhibits turnover of the tau protein by the proteasome: Influence of RCAN1 and oxidative stress. Biochemical Journal, 400(3), 511-520. https://doi.org/10.1042/BJ20060511
Qin, Y., Chen, L., Zhu, W., Song, J., Lin, J., Li, Y., ... & Qi, Y. (2024). TRIM37 is a primate-specific E3 ligase for Huntingtin and accounts for the striatal degeneration in Huntington's disease. Science Advances, 10(20), eadl2036. https://doi.org/10.1126/sciadv.adl2036
Riemenschneider, H., Guo, Q., Bader, J., Frottin, F., Farny, D., Kleinberger, G., ... & Edbauer, D. (2022). Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons. EMBO Reports, 23(5), e53890. https://doi.org/10.15252/embr.202153890
Saito, R., Kaneko, M., Okuma, Y., & Nomura, Y. (2010). Correlation between decrease in protein levels of ubiquitin ligase HRD1 and amyloid-β production. Journal of Pharmacological Sciences, 113(3), 285-288. https://doi.org/10.1254/jphs.10118sc
Schmidt, M., & Finley, D. (2014). Regulation of proteasome activity in health and disease. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1843(1), 13-25. https://doi.org/10.1016/j.bbamcr.2013.08.012
Soares, E. S., Martins, W. C., Tasca, C. I., & Cimarosti, H. (2022). Effects of protein post-translational modifications and SUMOylation on Huntington's disease. IBRO Neuroscience Reports, 12, 203-209. https://doi.org/10.1016/j.ibneur.2022.02.003
Stepanova, P., Eriksson, O., Voutilainen, M. H., & Lindholm, D. (2026). Corrigendum to "Animal models of Huntington's disease. Pros and cons" [Brain, Behavior, Immunity Health 50 (2025) 101149]. Brain, Behavior, & Immunity - Health, 52, 101180. https://doi.org/10.1016/j.bbih.2026.101180
Thibaudeau, T. A., Anderson, R. T., & Smith, D. M. (2018). A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers. Nature Communications, 9, 1097. https://doi.org/10.1038/s41467-018-03509-0
Trabolsi, C., & Cicchetti, F. (2026). Mutant huntingtin in the extracellular matrix: A new perspective on Huntington's disease pathology. Journal of Chemical Neuroanatomy, 136, 102470. https://doi.org/10.1016/j.jchemneu.2026.102470
Vasilopoulou, M. A., Ioannou, E., Roussis, V., & Chondrogianni, N. (2021). Modulation of the ubiquitin-proteasome system by marine natural products: A strategy to promote healthspan and longevity. Redox Biology, 41, 101897. https://doi.org/10.1016/j.redox.2021.101897
Yang, H., Zhong, X., Ballar, P., Luo, S., Shen, Y., Rubinsztein, D. C., ... & Fang, S. (2007). Ubiquitin ligase Hrd1 enhances the degradation and suppresses the toxicity of polyglutamine-expanded huntingtin. Experimental Cell Research, 313(3), 538-550. https://doi.org/10.1016/j.yexcr.2006.10.031
Yao, J.-Y., Liu, T., Hu, X.-R., Sheng, H., Chen, Z.-H., Zhao, H.-Y., Li, X. J., Wang, Y., & Hao, L. (2024). Allele-selective lowering of mutant HTT expression by targeting mutant HTT DNA, RNA and protein in Huntington's disease. Biomedicine & Pharmacotherapy, 180, 117557. https://doi.org/10.1016/j.biopha.2024.117557
Zhang, H., & Teplow, D. B. (2025). Cocktail gene therapy (CGT) for neurodegenerative diseases: Targeting protein clearance systems. Medical Hypotheses, 205, 111814. https://doi.org/10.1016/j.mehy.2025.111814
Zheng, Q., Song, B., Li, G., Cai, F., Wu, M., Zhao, Y., ... & Zhang, Z. (2022). USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Aβ generation. Journal of Clinical Investigation, 132(11), e152170. https://doi.org/10.1172/JCI152170