Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease
Abstract
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the gene encoding for huntingtin protein. A lot has been learned about this disease since its first description in 1872 and the identification of its causative gene and mutation in 1993. We now know that the disease is characterized by several molecular and cellular abnormalities whose precise timing and relative roles in pathogenesis have yet to be understood. HD is triggered by the mutant protein, and both gain-of-function (of the mutant protein) and loss-of-function (of the normal protein) mechanisms are involved. Here we review the data that describe the emergence of the ancient huntingtin gene and of the polyglutamine trait during the last 800 million years of evolution. We focus on the known functions of wild-type huntingtin that are fundamental for the survival and functioning of the brain neurons that predominantly degenerate in HD. We summarize data indicating how the loss of these beneficial activities reduces the ability of these neurons to survive. We also review the different mechanisms by which the mutation in huntingtin causes toxicity. This may arise both from cell-autonomous processes and dysfunction of neuronal circuitries. We then focus on novel therapeutical targets and pathways and on the attractive option to counteract HD at its primary source, i.e., by blocking the production of the mutant protein. Strategies and technologies used to screen for candidate HD biomarkers and their potential application are presented. Furthermore, we discuss the opportunities offered by intracerebral cell transplantation and the likely need for these multiple routes into therapies to converge at some point as, ideally, one would wish to stop the disease process and, at the same time, possibly replace the damaged neurons.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
HTT is involved in several cellular processes.
“HTT is involved in several cellular processes40, raising the potential for transcriptional changes downstream of HTT silencing (on-target vs off-target effects).”
From A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system (2019) · cites this paper as [40]
Cites
MACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366 · see citing works
Ravikumar, B., Vacher, C., Berger, Z., Davies, J. E., Luo, S., Oroz, L. G., Scaravilli, F., Easton, D. F., Duden, R., O'Kane, C. J., et al. (2004) · Nature Genetics · doi:10.1038/ng1362 · Cited by 2,347 · see citing works
Disease-Specific Induced Pluripotent Stem Cells.
Park, I.-H., Arora, N., Huo, H., Maherali, N., Ahfeldt, T., Shimamura, A., Lensch, M. W., Cowan, C., Hochedlinger, K., & Daley, G. Q. (2008) · Cell · doi:10.1016/j.cell.2008.07.041 · Cited by 2,196 · see citing works
Li, J.-Y., Englund, E., Holton, J. L., Soulet, D., Hagell, P., Lees, A. J., Lashley, T., Quinn, N. P., Rehncrona, S., Björklund, A., et al. (2008) · Nature Medicine · doi:10.1038/nm1746 · Cited by 1,845 · see citing works
Enriched environments, experience-dependent plasticity and disorders of the nervous system
Nithianantharajah, J., & Hannan, A. J. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1970 · Cited by 1,771 · see citing works
Direct brain infusion of glial cell line–derived neurotrophic factor in Parkinson disease
Gill, S. S., Patel, N. K., Hotton, G. R., O'Sullivan, K., McCarter, R., Bunnage, M., Brooks, D. J., Svendsen, C. N., & Heywood, P. (2003) · Nature Medicine · doi:10.1038/nm850 · Cited by 1,290 · see citing works
Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila
Steffan, J. S., Bodai, L., Pallos, J., Poelman, M., McCampbell, A., Apostol, B. L., Kazantsev, A., Schmidt, E., Zhu, Y.-Z., Greenwald, M., et al. (2001) · Nature · doi:10.1038/35099568 · Cited by 1,228 · see citing works
Mechanism of Human SIRT1 Activation by Resveratrol
Borra, M. T., Smith, B. C., & Denu, J. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501250200 · Cited by 1,065 · see citing works
Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines
Panov, A. V., Gutekunst, C.-A., Leavitt, B. R., Hayden, M. R., Burke, J. R., Strittmatter, W. J., & Greenamyre, J. T. (2002) · Nature Neuroscience · doi:10.1038/nn884 · Cited by 1,030 · see citing works
Browne, S. E., Bowling, A. C., Macgarvey, U., Baik, M. J., Berger, S. C., Muquit, M. M. K., Bird, E. D., & Beal, M. F. (1997) · Annals of Neurology · doi:10.1002/ana.410410514 · Cited by 885 · see citing works
Novel targets for Huntington's disease in an mTOR-independent autophagy pathway
Williams, A., Sarkar, S., Cuddon, P., Ttofi, E. K., Saiki, S., Siddiqi, F. H., Jahreiss, L., Fleming, A., Pask, D., Goldsmith, P., et al. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.79 · Cited by 800 · see citing works
Brain-derived Neurotrophic Factor Is Stored in Human Platelets and Released by Agonist Stimulation
Fujimura, H., Chen, R., Nakamura, T., Nakahashi, T., Kambayashi, J.-I., Sun, B., Altar, C., & Tandon, N. (2002) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1613072 · Cited by 777 · see citing works
Huntington disease: Clinical care and evaluation
Shoulson, I., & Fahn, S. (1979) · Neurology · doi:10.1212/wnl.29.1.1 · Cited by 746 · see citing works
Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington's Disease
Ferrante, R. J., Andreassen, O. A., Jenkins, B. G., Dedeoglu, A., Kuemmerle, S., Kubilus, J. K., Kaddurah-Daouk, R., Hersch, S. M., & Beal, M. F. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-12-04389.2000 · Cited by 522 · see citing works
Choo, Y. S. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh162 · Cited by 515 · cited 3× · see citing works
“It was suggested that mitochondrial calcium handling defects may be partly due to a direct deleterious effect of mutant huntingtin on the outer mitochondrial membrane, since incubation of normal mitochondria with the mutant protein reproduced the calcium-handling defect seen in human HD mitochondria (116, 426, 427).”
BackgroundMicroglial activation correlates with severity in Huntington disease: A clinical and PET study
Pavese, N., Gerhard, A., Tai, Y. F., Ho, A. K., Turkheimer, F., Barker, R. A., Brooks, D. J., & Piccini, P. (2006) · Neurology · doi:10.1212/01.wnl.0000222734.56412.17 · Cited by 462 · see citing works
Duan, W., Guo, Z., Jiang, H., Ware, M., Li, X.-J., & Mattson, M. P. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0536856100 · Cited by 428 · see citing works
Energy metabolism defects in Huntington's disease and effects of coenzyme Q<sub>10</sub>
Koroshetz, W. J., Jenkins, B. G., Rosen, B. R., & Beal, M. F. (1997) · Annals of Neurology · doi:10.1002/ana.410410206 · Cited by 405 · see citing works
Ferrante, R. J., Andreassen, O. A., Dedeoglu, A., Ferrante, K. L., Jenkins, B. G., Hersch, S. M., & Beal, M. F. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-05-01592.2002 · Cited by 391 · see citing works
Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2′dG
Hersch, S. M., Gevorkian, S., Marder, K., Moskowitz, C., Feigin, A., Cox, M., Como, P., Zimmerman, C., Lin, M., Zhang, L., et al. (2006) · Neurology · doi:10.1212/01.wnl.0000194318.74946.b6 · Cited by 313 · see citing works
The Huntington Study Group (2001) · Neurology · doi:10.1212/wnl.57.3.397 · Cited by 312 · see citing works
Outsourcing in the brain: Do neurons depend on cholesterol delivery by astrocytes?
Pfrieger, F. W. (2003) · BioEssays · doi:10.1002/bies.10195 · Cited by 308 · see citing works
Ochs, G., Penn, R. D., York, M., Giess, R., Beck, M., Tonn, J., Haigh, J., Malta, E., Traub, M., Sendtner, M., et al. (2000) · Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders · doi:10.1080/14660820050515197 · Cited by 302 · see citing works
Andreassen, O. A., Dedeoglu, A., Ferrante, R. J., Jenkins, B. G., Ferrante, K. L., Thomas, M., Friedlich, A., Browne, S. E., Schilling, G., Borchelt, D. R., et al. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2001.0406 · Cited by 293 · see citing works
Mitochondria and Huntington's Disease Pathogenesis: Insight from Genetic and Chemical Models
Browne, S. E. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1427.018 · Cited by 176 · see citing works
Synaptic dysfunction in Huntington's disease: a new perspective
Smith, R., Brundin, P., & Li, J.-Y. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5084-5 · Cited by 166 · see citing works
Mende-Mueller, L. M., Toneff, T., Hwang, S.-R., Chesselet, M.-F., & Hook, V. Y. H. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-06-01830.2001 · Cited by 163 · see citing works
Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington's disease mice
Stack, E. C., Smith, K. M., Ryu, H., Cormier, K., Chen, M., Hagerty, S. W., Del Signore, S. J., Cudkowicz, M. E., Friedlander, R. M., & Ferrante, R. J. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2005.11.002 · Cited by 114 · see citing works
Luthi-Carter, R., Apostol, B. L., Dunah, A. W., DeJohn, M. M., Farrell, L. A., Bates, G. P., Young, A. B., Standaert, D. G., Thompson, L. M., & Cha, J.-H. J. (2003) · Neurobiology of Disease · doi:10.1016/j.nbd.2003.08.024 · Cited by 104 · see citing works
del Toro, D., Canals, J. M., Ginés, S., Kojima, M., Egea, G., & Alberch, J. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3873-06.2006 · Cited by 95 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Brain-derived neurotrophic factor and its clinical Implications
Bathina, S., & Das, U. N. (2015) · Archives of Medical Science · doi:10.5114/aoms.2015.56342 · Cited by 1,381 · see citing works
Autophagy and apoptosis dysfunction in neurodegenerative disorders
Ghavami, S., Shojaei, S., Yeganeh, B., Ande, S. R., Jangamreddy, J. R., Mehrpour, M., Christoffersson, J., Chaabane, W., Moghadam, A. R., Kashani, H. H., et al. (2014) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2013.10.004 · Cited by 1,039 · see citing works
Neurogenesis in the striatum of the adult human brain
Ernst, A., Alkass, K., Bernard, S., Salehpour, M., Perl, S., Tisdale, J., Possnert, G., Druid, H., & Frisén, J. (2014) · Cell · doi:10.1016/j.cell.2014.01.044 · Cited by 937 · see citing works
Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications
Liu, Z., Zhou, T., Ziegler, A. C., Dimitrion, P., & Zuo, L. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/2525967 · Cited by 810 · see citing works
Potential function for the Huntingtin protein as a scaffold for selective autophagy
Ochaba, J., Lukacsovich, T., Csikos, G., Zheng, S., Margulis, J., Salazar, L., Mao, K., Lau, A. L., Yeung, S. Y., Humbert, S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1420103111 · Cited by 308 · see citing works
Lee, H., Fenster, R. J., Pineda, S. S., Gibbs, W. S., Mohammadi, S., Davila-Velderrain, J., Garcia, F. J., Therrien, M., Novis, H. S., Gao, F., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.06.021 · Cited by 279 · see citing works
Firefly luciferase mutants as sensors of proteome stress
Gupta, R., Kasturi, P., Bracher, A., Loew, C., Zheng, M., Villella, A., Garza, D., Hartl, F. U., & Raychaudhuri, S. (2011) · Nature Methods · doi:10.1038/nmeth.1697 · Cited by 219 · see citing works
Alterman, J. F., Godinho, B. M. D. C., Hassler, M. R., Ferguson, C. M., Echeverria, D., Sapp, E., Haraszti, R. A., Coles, A. H., Conroy, F., Miller, R., et al. (2019) · Nature Biotechnology · doi:10.1038/s41587-019-0205-0 · Cited by 227 · see citing works
Mutant huntingtin is present in neuronal grafts in huntington disease patients
Cicchetti, F., Lacroix, S., Cisbani, G., Vallières, N., Saint‐Pierre, M., St‐Amour, I., Tolouei, R., Skepper, J. N., Hauser, R. A., Mantovani, D., et al. (2014) · Annals of Neurology · doi:10.1002/ana.24174 · Cited by 193 · see citing works
Caffeine as a factor influencing the functioning of the human body-friend or foe?
Rodak, K., Kokot, I., & Kratz, E. M. (2021) · Nutrients · doi:10.3390/nu13093088 · Cited by 188 · see citing works
Lee, H., Noh, J.-Y., Oh, Y., Kim, Y., Chang, J.-W., Chung, C.-W., Lee, S.-T., Kim, M., Ryu, H., & Jung, Y.-K. (2012) · Human Molecular Genetics · doi:10.1093/hmg/ddr445 · Cited by 157 · see citing works
Godinho, B. M. D. C., Ogier, J. R., Darcy, R., O’Driscoll, C. M., & Cryan, J. F. (2013) · Molecular Pharmaceutics · doi:10.1021/mp3003946 · Cited by 126 · see citing works
(2018) · Handbook of Clinical Neurology · doi:10.1016/b978-0-444-63233-3.00017-8 · Cited by 122 · see citing works
Mehta, S. R., Tom, C. M., Wang, Y., Bresee, C., Rushton, D., Mathkar, P. P., Tang, J., & Mattis, V. B. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.09.076 · Cited by 112 · see citing works
Sagredo, O., Pazos, M. R., Satta, V., Ramos, J. A., Pertwee, R. G., & Fernández‐Ruiz, J. (2011) · Journal of Neuroscience Research · doi:10.1002/jnr.22682 · Cited by 105 · see citing works
Axonopathy in Huntington's disease
Li, J.-Y., & Conforti, L. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2012.08.010 · Cited by 55 · see citing works
The long and the short of aberrant ciliogenesis in Huntington disease
Liu, J.-P., & Zeitlin, S. O. (2011) · Journal of Clinical Investigation · doi:10.1172/jci60243 · Cited by 19 · see citing works
Morató, A., Elena-Real, C. A., Popovic, M., Fournet, A., Zhang, K., Allemand, F., Sibille, N., Urbanek, A., & Bernadó, P. (2020) · Biomolecules · doi:10.3390/biom10101458 · Cited by 12 · see citing works
McCollum, M. H., Leon, R. T., Rush, D. B., Guthrie, K. M., & Wei, J. (2013) · Brain Research · doi:10.1016/j.brainres.2013.04.030 · Cited by 11 · see citing works
“BDNF supplied by cortical afferents has been established as an important factor for the maintenance of striatal neurons in adults, and reduced levels of striatal BDNF have been demonstrated in both HD patients and animal models (Zuccato et al., 2010).”
Sorets, A. G., Schwensen, K. R., Francini, N., Kjar, A., Abdulrahman, A. M., Shostak, A., Katdare, K. A., Schoch, K. M., Cowell, R. P., Park, J. C., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf600 · Cited by 6 · see citing works
“…beyond the superficial layers of the brain adjacent to CSF. Transport to deeper brain structures is important because many diseases manifest in these sites, such as HD, which could prospectively be treated by lowering huntingtin (Htt) expression in medium spiny neurons of the striatum [ 7 ].”
- Authors
- Zuccato, C., Valenza, M., & Cattaneo, E.
- Affiliations
- University of Milan (IT)
- Venue
- Physiological Reviews
- Publisher
- American Physiological Society
- Published
- 2010-07
- Volume
- 90
- Issue
- 3
- Pages
- 905-981
- ISSN
- 0031-9333 (ISSN-L)
- 1522-1210
- OpenAlex
- W2029984090
- Cited by
- 848
- References
- 30
- Citations by year
- 2026: 20 · 2025: 35 · 2024: 29 · 2023: 29 · 2022: 37 · 2021: 36 · 2020: 35 · 2019: 50 · 2018: 61 · 2017: 66 · 2016: 69 · 2015: 67 · 2014: 93 · 2013: 77 · 2012: 78
- FWCI
- 6.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Physiological Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- Huntington's disease, huntingtin, CAG repeat expansion, polyglutamine, gain-of-function toxicity, neuronal survival, neurodegeneration, therapeutic target, biomarkers
- MeSH terms
- Huntingtin Protein, Animals, Brain, Cell Survival, Disease Models, Animal, Humans, Huntington Disease, Mutation, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Biomarkers, Gene Targeting
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
