Document Type : Review Article


1 Department of Biochemistry, University of Nigeria, Nsukka, Enugu, Nigeria

2 Department of Community Health Extension, School of Public Health/Nursing Technology, Nsukka, Enugu, Nigeria

3 Department of Applied Sciences, Federal College of Dental Technology and Therapy, Enugu, Nigeria



One of the leading causes of death apart from cancer is a neurodegenerative disease. Huntington's disease (HD) is such that affects the neurons resulting from the programmed degeneration of the nerve cells. It is expressed throughout the brain, most striking within the striatum and the cortex. The misfolded HD protein interrupts the other interacting proteins' activity resulting in the abnormal functioning of the nerve cells leading to the uncontrolled movements, loss of intellectual faculties, emotional disturbances categorizing motor dysfunctions, and behavioural and cognitive deficits. The genomic origin of the disease can be traced to the amplification of a cysteine-adenosine-guanine repeat that encodes a polyglutamine region in the huntingtin’s amino terminal end. However, the mechanism and modality in which cysteine-adenosine-guanine expansion leads to a poisonous effect on the neuron are yet to be clearly understood. However, studies have recently revealed that change in the blueprint (mRNA) of the protein gives rise to misfolded protein and the fragments accumulate, by making interaction with the other elements in cells resulting in the problems associated with HD. Hence, as opposed to the traditional and controversial protein misfolding hypothesis, amyloid formation is the result rather than the HD cause. Although, the N-terminal fragments of mutant huntingtin (mHtt) misfolded into amyloid-like fibrils as a key signature of HD pathology. Currently, no effective remedy has been found for HD. This review highlights the possible cause, pathogenesis, and recent therapy aiming at down-regulating the expression of huntingtin (Htt), lowering the misfolding, and aggregation of the huntingtin protein. 

Graphical Abstract

Huntington Disease: Mechanism of Pathogenesis and Recent Developments in Its Therapeutic Strategies-A Short Review


[1]   Y.T. Wang, J.H. Lu, Chaperone-mediated autophagy in neurodegenerative diseases: molecular mechanisms and pharmacological opportunities, Cells, 2022, 11, 2250. [Crossref], [Google Scholar], [Publisher]
[2]   اR. Baker, S.L. Mason, The hunt for better treatment for huntington’s disease, The Lancet Neurology, 2019, 18, 1–6. [Crossref], [Google Scholar], [Publisher]
[3]   S. Dutta, Huntington's disease: From molecular pathogenesis to clinical treatment, International Journal of Drug Research and Technology, 2015, 5, 112–128. [Crossref], [Publisher]
[4]   P. Gonzalez-Alegre, A.K. Afifi, Clinical characteristics of childhood-onset (juvenile) Huntington disease: Report of 12 patients and review of the literature, Journal of child neurology, 2006, 21, 223–229. [Crossref], [Google Scholar], [Publisher]
[5]   M.S. Yu, N. Tanese, Huntingtin is required for neural but not cardiac/pancreatic progenitor differentiation of mouse embryonic stem cells in vitro, Frontiers in cellular neuroscience, 2017, 11, 1–16. [Crossref], [Google Scholar], [Publisher]
[6]   V.K. Sharma, D. Shimla, H. Pradesh, Huntington’s Disease : Clinical Complexities and Therapeutic Strategies, Journal of Advanced scientific research, 2012, 3, 29–36. [Google Scholar], [Publisher]
[7]   K.M. Biglan, Y. Zhang, J.D. Long, M. Geschwind, G.A. Kang, A. Killoran, W. Lu, E. McCusker, J.A. Mills, L.A. Raymond, C. Testa, Refining the diagnosis of huntington disease: The PREDICT-HD study, Frontiers in aging neuroscience, 2013, 5, 1–8. [Crossref], [Google Scholar], [Publisher]
[8]   L. Naia, M.J. Ribeiro, A.C. Rego, Mitochondrial and metabolic-based protective strategies in Huntington’s disease: the case of creatine and coenzyme Q, 2012, 23, 13-28. [Crossref], [Google Scholar], [Publisher]
[9]   M.D. Rawlins et al., The prevalence of huntington’s disease, Neuroepidemiology, 2016, 46, 144–153. [Crossref], [Google Scholar], [Publisher]
[10] M. Riccò, L. Vezzosi, F. Balzarini, G. Gualerzi, S. Ranzieri, Prevalence of huntington disease in Italy: A systematic review and meta-analysis, Acta Bio Medica: Atenei Parmensis, 2020, 91, 119–127. [Crossref], [Google Scholar], [Publisher]
[11] S. Ramaswamy, K.M. Shannon, J.H. Kordower, Huntington's disease: pathological mechanisms and therapeutic strategies, Cell transplantation, 2007, 16, 301-312. [Crossref], [Google Scholar], [Publisher]
[12] E.B. Clabough, Huntington’s disease: the past, present, and future search for disease modifiers, Yale journal of biology and medicine, 2013, 86, 217-233. [Crossref], [Google Scholar], [Publisher]
[13] J. Schulte, J.T. Littleton, The biological function of the Huntingtin protein and its relevance to Huntington’s Disease pathology, Current Trends in Neurology, 2011, 1, 65-78. [Crossref], [Google Scholar], [Publisher]
[14] J. Labbadia, R.I. Morimoto, Huntington’s disease: underlying molecular mechanisms and emerging concepts, Trends in biochemical sciences, 2013, 38, 378–385. [Crossref], [Google Scholar], [Publisher]
[15] L. Roller, J. Gowan, Huntington’s disease, Aust. J. Pharm., 2018, 99, 90–99. [Crossref], [Google Scholar], [Publisher]
[16] J. Ko, J.M. Isas, A. Sabbaugh, J.H. Yoo, N.K. Pandey, A. Chongtham, M. Ladinsky, W.L. Wu, H. Rohweder, A. Weiss, D. Macdonald, Identification of distinct conformations associated with monomers and fibril assemblies of mutant huntingtin, Human molecular genetics, 2018, 27, 2330–2343. [Crossref], [Google Scholar], [Publisher]
[17] J.K. Jopling, C.C. Sheckter, B.C. James, CRISPR takes on Huntington’s disease, Annals of Surgery, 2018, 267, 817–819. [Crossref], [Google Scholar], [Publisher]
[18] M. Nasrullah, Huntington’S Disease: Understanding the Pathophysiology Through the Huntingtin Gene, Indo American Journal of Pharmaceutical Sciences, 2018, 5, 534–541. [Crossref], [Google Scholar], [Publisher]
[19] A.C. Bachoud-Lévi, J. Ferreira, R. Massart, K. Youssov, A. Rosser, M. Busse, D. Craufurd, R. Reilmann, G. De Michele, D. Rae, F. Squitieri, International guidelines for the treatment of Huntington’s disease, Frontiers in neurology, 2019, 10, 710. [Crossref], [Google Scholar], [Publisher]
[20] S. Frank, Treatment of Huntington’s Disease, Neurotherapeutics, 2014, 11, 153–160. [Crossref], [Google Scholar], [Publisher]
[21] K. M. Shannon and A. Fraint, Therapeutic advances in Huntington’s Disease, Movement Disorders, 2015, 30, 1539–1546. [Crossref], [Google Scholar], [Publisher]
[22] J. Caboche, D. Charvin, Role of dopamine in Huntington’s disease, M/S: médecine sciences, 2006, 22, 115–117. [Crossref], [Google Scholar], [Publisher]
[23] C. Cepeda, K.P.S. Murphy, M. Parent, M.S. Levine, The Role of Dopamine in Huntington’s Disease Striatal DA Innervation in the HD Postmortem Brain, Progress in Brain Research, 2014, 211, 235–254. [Crossref], [Google Scholar], [Publisher]
[24] A. Chatterjee, S. Saha, A. Chakraborty, A. Silva-Fernandes, S.M. Mandal, A. Neves-Carvalho, Y. Liu, R.K. Pandita, M.L. Hegde, P.M. Hegde, I. Boldogh, T. Ashizawa, A.H. Koeppen, T.K. Pandita, P. Maciel, P.S. Sarkar, T.K. Hazra, The Role of the Mammalian DNA End-processing Enzyme Polynucleotide Kinase 3’-Phosphatase in Spinocerebellar Ataxia Type 3 Pathogenesis, Plos genetics, 2015, 11, e1004749. [Crossref], [Google Scholar], [Publisher]
[25] R. Gao, Y. Liu, A. Silva-Fernandes, X. Fang, A. Paulucci-Holthauzen, A. Chatterjee, H.L. Zhang, T. Matsuura, S. Choudhary, T. Ashizawa, A.H. Koeppen, P. Maciel, T.K. Hazra, P.S. Sarkar, Inactivation of PNKP by Mutant ATXN3 Triggers Apoptosis by Activating the DNA Damage-Response Pathway in SCA3, Plos genetics, 2015, 11, e1004834. [Crossref], [Google Scholar], [Publisher]
[26] R. Morigaki, S. Goto, Striatal vulnerability in huntington’s disease: Neuroprotection versus neurotoxicity, Brain sciences, 2017, 7, 63. [Crossref], [Google Scholar], [Publisher]
[27] Lieberman O.J., McGuirt A.F., Tang G., Sulzer D., Roles for neuronal and microglial autophagy in synaptic pruning during development, Neurobiology of Disease, 2019, 32, 981–984. [Crossref], [Google Scholar], [Publisher]
[28] I.B. Reddy, D. Kaladhar, G. Santhosh, A.K. Chaitanya, Huntingtin protein modeling and structure alignment studies, International Journal of Pharma and Bio Sciences, 2011, 2, 147–152. [Google Scholar]
[29] P. Langfelder, F. Gao, N. Wang, D. Howland, S. Kwak, T.F. Vogt, J.S. Aaronson, J. Rosinski, G. Coppola, S. Horvath, X.W. Yang, MicroRNA signatures of endogenous Huntingtin CAG repeat expansion in mice, PLoS One, 2018, 13, e0190550. [Crossref], [Google Scholar], [Publisher]
[30] D.J.H. Moss, A.F. Pardiñas, D. Langbehn, K. Lo, B.R. Leavitt, R. Roos, A. Durr, S. Mead, A. Coleman, R.D. Santos, J. Decolongon, Identification of genetic variants associated with Huntington’s disease progression: a genome-wide association study, The Lancet Neurology, 2017, 16, 701–711. [Crossref], [Google Scholar], [Publisher]
[31] N.S. Caron, E.R. Dorsey, M.R. Hayden, Therapeutic approaches to huntington disease: From the bench to the clinic, Nature Reviews Drug Discovery, 2018, 17, 729–750. [Crossref], [Google Scholar], [Publisher]
[32] S. Kim, K.T. Kim, Therapeutic Approaches for Inhibition of Protein Aggregation in Huntington’s Disease, Experimental neurobiology, 2014, 23, 36–44. [Crossref], [Google Scholar], [Publisher]
[33] M. Arrasate, S. Finkbeiner, Protein aggregates in Huntington’s disease, Experimental neurology, 2012, 238, 1–11. [Crossref], [Google Scholar], [Publisher]
[34] K. Sathasivam, A. Neueder, T.A. Gipson, C. Landles, A.C. Benjamin, M.K. Bondulich, D.L. Smith, R.L. Faull, R.A. Roos, D. Howland, P.J. Detloff, Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease, Proceedings of the National Academy of Sciences, 2013, 110, 2366–2370. [Crossref], [Google Scholar], [Publisher]
[35] A. Neueder, C. Landles, R. Ghosh, D. Howland, R.H. Myers, R.L. Faull, S.J. Tabrizi, G.P. Bates, The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington ’ s disease patients, Scientific reports, 2017, 7, 1307. [Crossref], [Google Scholar], [Publisher]
[36] M. Bañez-Coronel, S. Porta, B. Kagerbauer, E. Mateu-Huertas, L. Pantano, I. Ferrer, M. Guzmán, X. Estivill, E. Martí, A pathogenic mechanism in huntington’s disease involves small CAG-repeated RNAs with neurotoxic activity, PLoS genetics, 2012, 8, e1002481. [Crossref], [Google Scholar], [Publisher]
[37] M. Bañez-Coronel, F. Ayhan, A.D. Tarabochia, T. Zu, B.A. Perez, S.K. Tusi, O. Pletnikova, D.R. Borchelt, C.A. Ross, R.L. Margolis, A.T. Yachnis, RAN Translation in Huntington Disease, Neuron, 2015, 88, 667–677. [Crossref], [Google Scholar], [Publisher]
[38] J. Leitman, F. Ulrich Hartl, G.Z. Lederkremer, Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress, Nature communications, 2013, 4, 2753. [Crossref], [Google Scholar], [Publisher]
[39] T. Takeuchi, Y. Nagai, Protein misfolding and aggregation as a therapeutic target for polyglutamine diseases, Brain sciences, 2017, 7, 128. [Crossref], [Google Scholar], [Publisher]
[40] M.A. Mason, C. Gomez-Paredes, K. Sathasivam, A. Neueder, A.S. Papadopoulou, G.P..Bates, Silencing Srsf6 does not modulate incomplete splicing of the huntingtin gene in Huntington’s disease models, Scientific Reports, 2020, 10, 14057. [Crossref], [Google Scholar], [Publisher]
[41] Milewski M., Hoffman-Zacharska D., Ball J., Molecular therapeutic strategies for Huntington’s disease, Postepy Biochemii, 2015, 61, 18-24. [Google Scholar], [Publisher]
[42] R.I. Scahill, E.J. Wild, S.J. Tabrizi, Biomarkers for Huntington’s disease : An update Biomarkers for Huntington’s disease : an update, Expert opinion on medical diagnostics, 2017, 6, 371-375. [Crossref], [Google Scholar], [Publisher]
[43] F. Mahjoubi, M. Montazeri, S. Zare-kahrizi, S. Nafisi, and G. Engineering, Employing Real Time PCR for the Diagnosis of Huntington Disease, Zahedan Journal Of Research In Medical Sciences, 2013, 15, e92924. [Google Scholar], [Publisher]
[44] R.L. Margolis, C.A. Ross, Diagnosis of Huntington disease, Clinical Chemistry, 2003, 49, 1726–1732. [Crossref], [Google Scholar], [Publisher]
[45] C.A. Gutekunst, S.H. Li, H. Yi, J.S. Mulroy, S. Kuemmerle, R. Jones, D. Rye, R.J. Ferrante, S.M. Hersch, X.J. Li, Nuclear and neuropil aggregates in Huntington’s disease: Relationship to neuropathology, Journal of Neuroscience, 1999, 19, 2522–2534. [Crossref], [Google Scholar], [Publisher]
[46] I. Kanazawa, D. Ph, Therapeutic Strategies in Huntington’s Disease, 2006, 2, 213–224. [Crossref], [Google Scholar], [Publisher]
[47] E.A. Thomas, G. Coppola, P.A. Desplats, B. Tang, E. Soragni, R. Burnett, F. Gao, K.M. Fitzgerald, J.F. Borok, D. Herman, D.H. Geschwind, The HDAC inhibitor 4b ameliorates the disease phenotype and transcriptional abnormalities in Huntington’s disease transgenic mice, Proceedings of the National Academy of Sciences, 2008, 105, 15564–15569. [Crossref], [Google Scholar], [Publisher]
[48] F.H. Qureshi, S.H. Qureshi, T. Zia, F. Khawaja, Huntington’S Disease (Hd): a Brief Review, European Journal of Public Health Studies, 2022, 5, 74–93. [Crossref], [Google Scholar], [Publisher]
[49] A.M. Monteys, S.A. Ebanks, M.S. Keiser, B.L. Davidson, CRISPR/Cas9 Editing of the Mutant Huntingtin Allele In Vitro and In Vivo, Molecular Therapy, 2017, 25, 12–23. [Crossref], [Google Scholar], [Publisher]
[50] A. Deb, S. Frank, C.M. Testa, New symptomatic therapies for Huntington disease, Handbook of clinical neurology, 2017, 144, 199-207.[Crossref], [Google Scholar], [Publisher]
[51] Hassaan Bashir, Emerging therapies in Huntington’s disease Expert Review of Neurotherapeutics, 2019, 19, 983-995. [Crossref], [Google Scholar], [Publisher]
[52] S.K. Saha, F.K. Saikot, M.S. Rahman, M.A.H.M. Jamal, S.K. Rahman, S.R. Islam, K.H. Kim, Programmable Molecular Scissors : Applications of a New Tool for Genome Editing in Biotech, Molecular Therapy-Nucleic Acids, 2019, 14, 212–238. [Crossref], [Google Scholar], [Publisher]
[53] A. Karimian, K. Azizian, H. Parsian, S. Rafieian, V. Shafiei‐Irannejad, M. Kheyrollah, M. Yousefi, M. Majidinia, B. Yousefi, CRISPR / Cas9 technology as a potent molecular tool for gene therapy, Journal of Cellular Physiology, 2019, 234, 12267-12277. [Crossref], [Google Scholar], [Publisher]
[54] D. Kwon, Genetic therapies for Huntington’s disease fail in clinical trials, Nature, 2021, 593, 180. [Google Scholar], [Publisher]
[55] M.W. Ferguson, C.J. Kennedy, T.H. Palpagama, H.J. Waldvogel, R.L. Faull, A. Kwakowsky, Current and Possible Future Therapeutic Options for Huntington’s Disease, Journal of Central Nervous System Disease, 2022, 14, p. 117957352210925. [Crossref], [Google Scholar], [Publisher]
[56] Heinz G.A., Mashreghi M.F., CRISPR-Cas-System als molekulare Schere für Gentherapie, Zeitschrift für Rheumatologie, 2017, 76, 46-49. [Crossref], [Google Scholar], [Publisher]
[57] S. Maity, P. Komal, V. Kumar, A. Saxena, A. Tungekar, and V. Chandrasekar, Impact of ER Stress and ER-Mitochondrial Crosstalk in Huntington’s Disease, International Journal of Molecular Sciences, 2022, 23, 780. [Crossref], [Google Scholar], [Publisher]
[58] M. Broeders, P. Herrero-Hernandez, M.P. T. Ernst, A.T. van der Ploeg, W.W.M.P. Pijnappel, Sharpening the Molecular Scissors: Advances in Gene-Editing Technology, IScience, 2020, 23, 100789. [Crossref], [Google Scholar], [Publisher]
[59] E. Davis, Genome Editing: Which Should I Choose, TALEN or CRISPR?, Gene Copoeia, Expressway to Discovery, 2013, 1–5. [Crossref], [Publisher]
[60] S. Becker, J. Boch, TALE and TALEN genome editing technologies, Gene and Genome Editing, 2021, 2, 100007. [Crossref], [Google Scholar], [Publisher]
[61] P. Mali, L. Yang, K.M. Esvelt, J. Aach, M. Guell, J.E. DiCarlo, J.E. Norville, G.M. Church, RNA-guided human genome engineering via Cas9, Science, 2013, 339, 823-826. [Google Scholar], [Publisher]
[62] A. Malzahn, L. Lowder, Y. Qi, Plant genome editing with TALEN and CRISPR, Cell & bioscience, 2017, 7, 1–18. [Crossref], [Google Scholar], [Publisher]
[63] T. Shacham, N. Sharma, G.Z. Lederkremer, Protein misfolding and ER stress in Huntington’s disease, Frontiers in molecular biosciences, 2019, 6, 1–12. [Crossref], [Google Scholar], [Publisher]
[64] E.M. Sontag, G.P. Lotz, N. Agrawal, A. Tran, R. Aron, G. Yang, M. Necula, A. Lau, S. Finkbeiner, C. Glabe, J.L. Marsh, P.J. Muchowski, L.M. Thompson, Methylene blue modulates Huntingtin aggregation intermediates and is protective in Huntington’s disease models, Journal of Neuroscience, 2012, 32, 11109–11119. [Crossref], [Google Scholar], [Publisher]
[65] R.N. Hegde, A. Chiki, L. Petricca, P. Martufi, N. Arbez, L. Mouchiroud, J. Auwerx, C. Landles, G.P. Bates, M.K. Singh‐Bains, M. Dragunow, TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington’s disease models, The EMBO journal, 2020, 39, e104671. [Crossref], [Google Scholar], [Publisher]
[66] L.E. Bowie, T. Maiuri, M. Alpaugh, M. Gabriel, N. Arbez, D. Galleguillos, C.L. Hung, S. Patel, J. Xia, N.T. Hertz, C.A. Ross, N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation, Proceedings of the National Academy of Sciences, 2018, 115, E7081–E7090. [Crossref], [Google Scholar], [Publisher]
[67] L.E. Bowie, T. Maiuri, M. Alpaugh, M. Gabriel, N. Arbez, D. Galleguillos, C.L. Hung, S. Patel, J. Xia, N.T. Hertz, C.A. Ross, N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation, Proceedings of the National Academy of Sciences, 2018, 115, E7081-E7090. [Crossref], [Google Scholar], [Publisher]