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image of The Role of Animal Models in Huntington's Disease Clinical Trials: Decoding Genetic, Non-Genetic, and Molecular Pathways

Abstract

Background

Huntington's disease (HD) is a neurodegenerative disorder due to a CAG trinucleotide repeat expansion in the HD gene. Animal models have been instrumental in revealing the genetic and molecular bases of HD. While animal models cannot exactly model the human disease because of anatomical and lifespan differences, they are essential in revealing HD pathology and possible treatments.

Objective

This review aimed to highlight the significance of animal models, particularly rodents, in deepening our knowledge of Huntington's disease. It underlines how non-genetic and genetic models have aided research and therapy innovation as well as their limitations.

Methods

This review addresses the use of different models of animals, including genetic models, such as transgenic mice and non-genetic models, for example, invertebrates and non-human primates. It addresses the creation of these models through methods, such as gene transfer techniques and transgenic manipulation, to simulate the genetic defects that occur in humans. The applicability of model choice based on validity criteria, including symptom manifestation and treatment effectiveness, is also discussed.

Results

This study underscores the effectiveness of the R6/2 mouse model, characterized by accelerated symptom onset and HD pathology. Progress in genetic engineering has also boosted the construction of murine and rat models that reproduce the hereditary aspects of HD, providing significant platforms for experimental investigation.

Conclusion

Even with their limitations, animal models, especially rodents, continue to play a vital role in the study of HD pathogenesis and therapeutic intervention. These models still shed light on the disease and direct towards the identification of effective treatments.

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2025-07-07
2025-10-31

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References

  1. Rubinsztein D.C. Lessons from animal prototypes of HD. Trends Genet. 2002 18 4 202 209 10.1016/S0168‑9525(01)02625‑7 11932021
    [Google Scholar]
  2. Li J.Y. Popovic N. Brundin P. The use of the R6 transgenic MD of HD in attempts to develop novel therapeutic approaches. NeuroRx 2005 2 3 447 464 10.1602/neurorx.2.3.447 16389308
    [Google Scholar]
  3. Morton A.J. Howland D.S. Large genetic animal prototypes of HD. J. Huntingtons Dis. 2013 2 1 3 19 10.3233/JHD‑130050 25063426
    [Google Scholar]
  4. Menalled L.B. Chesselet M.F. MD of HD. Trends Pharmacol. Sci. 2002 23 1 32 39 10.1016/S0165‑6147(00)01884‑8 11804649
    [Google Scholar]
  5. Ferrante R.J. MD of HD and methodological considerations for therapeutic trials. Biochim. Biophys. Acta Mol. Basis Dis. 2009 1792 6 506 520 10.1016/j.bbadis.2009.04.001 19362590
    [Google Scholar]
  6. Brignull H.R. Morley J.F. Garcia S.M. Morimoto R.I. Modeling polyglutamine pathogenesis in C. elegans. Methods Enzymol. 2006 412 256 282 10.1016/S0076‑6879(06)12016‑9 17046663
    [Google Scholar]
  7. Tkacs N.C. Thompson H.J. From bedside to bench and back again: Research issues in animal prototypes of person ailment. Biol. Res. Nurs. 2006 8 1 78 88 10.1177/1099800406289717 16766631
    [Google Scholar]
  8. Greek R. Rice M.J. Animal models and conserved processes. Theor. Biol. Med. Model. 2012 9 1 40 10.1186/1742‑4682‑9‑40 22963674
    [Google Scholar]
  9. Li X.J. Li S. Large animal prototypes of HD. Curr. Top. Behav. Neurosci. 2015 22 149 160 10.1007/7854_2013_246 24048953
    [Google Scholar]
  10. Ehrnhoefer D.E. Butland S.L. Pouladi M.A. Hayden M.R. MD of HD: Variations on a theme. Dis. Model. Mech. 2009 2 3-4 123 129 10.1242/dmm.002451 19259385
    [Google Scholar]
  11. Crook Z.R. Housman D. Huntington’s disease: Can mice lead the way to treatment? Neuron 2011 69 3 423 435 10.1016/j.neuron.2010.12.035 21315254
    [Google Scholar]
  12. Naver B. Stub C. Møller M. Fenger K. Hansen A.K. Hasholt L. Molecular and behavioral analysis of the R6/1 HD transgenic mouse. Neurosci 2003 122 4 1049 1057 10.1016/j.neuroscience.2003.08.053 14643771
    [Google Scholar]
  13. Mangiarini L. Sathasivam K. Seller M. Cozens B. Harper A. Hetherington C. Exon 1 of the HD gene through an expanded CAG recurrence is sufficient to cause a progressive neurological make-up in transgenic mice. Cell 1996 87 3 493 06 10.1016/S0092‑8674(00)81369‑0 8898202
    [Google Scholar]
  14. Davies S.W. Turmaine M. Cozens B.A. DiFiglia M. Sharp A.H. Ross C.A. Scherzinger E. Wanker E.E. Mangiarini L. Bates G.P. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997 90 3 537 548 10.1016/S0092‑8674(00)80513‑9 9267033
    [Google Scholar]
  15. Guidetti P. Bates G.P. Graham R.K. Hayden M.R. Leavitt B.R. MacDonald M.E. Elevated brain 3-hydroxykynurenine and quinolinate stages in HD mice. Neurobiol. Dis. 2006 23 1 190 197 10.1016/j.nbd.2006.02.011 16697652
    [Google Scholar]
  16. Sathyasaikumar K.V. Stachowski E.K. Amori L. Guidetti P. Muchowski P.J. Schwarcz R. Dysfunctional kynurenine pathway metabolism in the R6/2 MD of HD. J. Neurochem. 2010 113 6 1416 1425 10.1111/j.1471‑4159.2010.06675.x 20236387
    [Google Scholar]
  17. Von Horsten S. Schmitt I. Nguyen H.P. Holzmann C. Schmidt T. Walther T. Transgenic rat model of HD. Hum. Mol. Genet. 2003 12 6 617 624 10.1093/hmg/ddg075 12620967
    [Google Scholar]
  18. File S.E. Mahal A. Mangiarini L. Bates G.P. Striking changes in anxiety in HD transgenic mice. Brain Res. 1998 805 1-2 234 240 10.1016/S0006‑8993(98)00736‑7 9733972
    [Google Scholar]
  19. Young A.B. Penney J.B. Starosta-Rubinstein S. Markel D.S. Berent S. Giordani B. PET scan investigations of HD: Cerebral metabolic correlates of neurological features and functional decline. Ann. Neurol. 1986 20 3 296 03 10.1002/ana.410200305 2945510
    [Google Scholar]
  20. Fielding S.A. Brooks S.P. Klein A. Bayram-Weston Z. Jones L. Dunnett S.B. Profiles of motor and cognitive impairment in the transgenic rat model of HD. Brain Res. Bull. 2012 88 2-3 223 236 10.1016/j.brainresbull.2011.09.011 21963415
    [Google Scholar]
  21. Mazurova Y. Anderova M. Nemecková I. Bezrouk A. Transgenic rat model of HD: A histopathological study and correlations through neurodegenerative process in the brain of HD case. BioMed Res. Int. 2014 2014 291531 10.1155/2014/291531 25162006
    [Google Scholar]
  22. Slow E.J. van Raamsdonk J. Rogers D. Coleman S.H. Graham R.K. Deng Y. Selective striatal neuronal loss in a YAC128 MD of HD. Hum. Mol. Genet. 2003 12 13 1555 1567 10.1093/hmg/ddg169 12812983
    [Google Scholar]
  23. Van Raamsdonk J.M. Warusing S.C. Hayden M.R. Selective degeneration in YAC MD of HD. Brain Res. Bull. 2007 72 2-3 124 131 10.1016/j.brainresbull.2006.10.018 17352936
    [Google Scholar]
  24. Hodgson J.G. Agopyan N. Gutekunst C.A. Leavitt B.R. LePiane F. Singaraja R. A YAC MD for HD through full-length mutant HTT, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 1999 23 1 181 192 10.1016/S0896‑6273(00)80764‑3 10402204
    [Google Scholar]
  25. Schwarcz R. Guidetti P. Sathyasaikumar K.V. Muchowski P.J. Of mice, rats and men: Revisiting the QA hypothesis of HD. Prog. Neurobiol. 2010 90 2 230 245 10.1016/j.pneurobio.2009.04.005 19394403
    [Google Scholar]
  26. Heintz N. Bac to the future: The use of bac transgenic mice for neuroscience research. Nat. Rev. Neurosci. 2001 2 12 861 870 10.1038/35104049 11733793
    [Google Scholar]
  27. Wegrzynowicz M. Bichell T.J. Soares B.D. Loth M.K. McGlothan J.S. Mori S. Novel BAC MD of HD through 225 CAG Recurrences Exhibits an Early Widespread and Stable Degenerative Make-up. J. Huntingtons Dis. 2015 4 1 17 36 10.3233/JHD‑140116 26333255
    [Google Scholar]
  28. Abada Y.K. Nguyen H.P. Schreiber R. Ellenbroek B. Assessment of motor function, sensory motor gating and recognition memory in a novel BACHD transgenic rat model for huntington disease. PLoS One 2013 8 7 68584 10.1371/journal.pone.0068584 23874679
    [Google Scholar]
  29. Yu-Taeger L. Petrasch-Parwez E. Osmand A.P. Redensek A. Metzger S. Clemens L.E. Park L. Howland D. Calaminus C. Gu X. Pichler B. Yang X.W. Riess O. Nguyen H.P. A novel BACHD transgenic rat exhibits characteristic neuropathological features of Huntington disease. J. Neurosci. 2012 32 44 15426 15438 10.1523/JNEUROSCI.1148‑12.2012 23115180
    [Google Scholar]
  30. Menalled L.B.K.I. MD of HD. NeuroRx 2005 2 3 465 470 10.1602/neurorx.2.3.465 16389309
    [Google Scholar]
  31. Martindale D. Hackam A. Wieczorek A. Ellerby L. Wellington C. McCutcheon K. Singaraja R. Kazemi-Esfarjani P. Devon R. Kim S.U. Bredesen D.E. Tufaro F. Hayden M.R. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat. Genet. 1998 18 2 150 154 10.1038/ng0298‑150 9462744
    [Google Scholar]
  32. Wheeler V.C. Auerbach W. White J.K. Srinidhi J. Auerbach A. Ryan A. Length-dependent gametic CAG recurrence instability in the HD KI mouse. Hum. Mol. Genet. 1999 8 1 115 122 10.1093/hmg/8.1.115 9887339
    [Google Scholar]
  33. Yu Z.X. Li S.H. Evans J. Pillarisetti A. Li H. Li X.J. Mutant HTT causes context-dependent neurodegeneration in mice through HD. J. Neurosci. 2003 23 6 2193 2202 10.1523/JNEUROSCI.23‑06‑02193.2003 12657678
    [Google Scholar]
  34. Schilling G. Becher M.W. Sharp A.H. Jinnah H.A. Duan K. Kotzuk J.A. Slunt H.H. Ratovitski T. Cooper J.K. Jenkins N.A. Copeland N.G. Price D.L. Ross C.A. Borchelt D.R. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum. Mol. Genet. 1999 8 3 397 407 9949199
    [Google Scholar]
  35. Hansson O. Castilho R.F. Korhonen L. Lindholm D. Bates G.P. Brundin P. Partial resistance to malonate-induced striatal cell demise in transgenic MD of HD is dependent on age and CAG recurrence length. J. Neurochem. 2001 78 4 694 03 11520890
    [Google Scholar]
  36. Lee C.Y. Cantle J.P. Yang X.W. Genetic manipulations of mutant HTT in mice: New insights into HD focalization. FEBS J. 2013 280 18 4382 4394 10.1111/febs.12418 23829302
    [Google Scholar]
  37. McBride J.L. Ramaswamy S. Gasmi M. Bartus R.T. Herzog C.D. Brandon E.P. Viral delivery of glial cell line-derived neurotrophic factor improves behavior and protects striatal neurons in a MD of HD. Proc. Natl. Acad. Sci. USA 2006 103 24 9345 9350 10.1073/pnas.0508875103 16751280
    [Google Scholar]
  38. Ramaswamy S. McBride J.L. Kordower J.H. Animal prototypes of HD. ILAR J. 2007 48 4 356 373 10.1093/ilar.48.4.356 17712222
    [Google Scholar]
  39. Shin J.Y. Fang Z.H. Yu Z.X. Wang C.E. Li S.H. Li X.J. Expression of mutant huntingtin in glial cells contributes to neuronal excitotoxicity. J. Cell Biol. 2005 171 6 1001 1012 10.1083/jcb.200508072 16365166
    [Google Scholar]
  40. Murakami S. Takemoto T. Shimizu S. Studies on the effective principles of Diagenea simplex Aq. I Separation of the effective fraction using liquid chromatography. J Pharm Soc Jpn 1953 73 1026 1028 10.1248/yakushi1947.73.9_1026
    [Google Scholar]
  41. Lévesque M. Avoli M. The kainic acid model of temporal lobe epilepsy. Neurosci. Biobehav. Rev. 2013 37 10 2887 2899 10.1016/j.neubiorev.2013.10.011 24184743
    [Google Scholar]
  42. Ferrante R.J. Kowall N.W. Beal M.F. Richardson E.P. Jr Bird E.D. Martin J.B. Selective sparing of a class of striatal neurons in HD. Sci 1985 230 4725 561 563 10.1126/science.2931802 2931802
    [Google Scholar]
  43. Coyle J.T. Schwarcz R. Lesion of striatal neurons with kainic acid provides a model for Huntington’s chorea. Nature 1976 263 5574 244 246 10.1038/263244a0 8731
    [Google Scholar]
  44. Foster A. Collins J.F. Schwarcz R. On the excitotoxic properties of quinolinic acid, 2,3-piperidine dicarboxylic acids and structurally related compounds. Neuropharmacology 1983 22 12 1331 1342 10.1016/0028‑3908(83)90221‑6 6229703
    [Google Scholar]
  45. Hantraye P. Riche D. Maziere M. Isacson O. A primate model of HD: Behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon. Exp. Neurol. 1990 108 2 91 104 10.1016/0014‑4886(90)90014‑J 2139853
    [Google Scholar]
  46. Coyle J.T. Schwarcz R. Bennett J.P. Campochiaro P. Clinical, neuropathologic and pharmacologic aspects of HD: Correlates through a new animal prototype. Prog. Neuropsychopharmacol. 1977 1 1-2 13 30 10.1016/0364‑7722(77)90025‑X 214805
    [Google Scholar]
  47. DiFiglia M. Excitotoxic injury of the neostriatum: A model for HD. Trends Neurosci. 1990 13 7 286 289 10.1016/0166‑2236(90)90111‑M 1695405
    [Google Scholar]
  48. Bruyn R.P.M. Stoof J.C. The quinolinic acid hypothesis in Huntington’s chorea. J. Neurol. Sci. 1990 95 1 29 38 10.1016/0022‑510X(90)90114‑3 2159984
    [Google Scholar]
  49. Schwarcz R. Whetsell W.O. Jr Mangano R.M. Quinolinic acid: An endogenous metabolite that produces axon-sparing lesions in rat brain. Science 1983 219 4582 316 318 10.1126/science.6849138 6849138
    [Google Scholar]
  50. Beal M.F. Kowall N.W. Ellison D.W. Mazurek M.F. Swartz K.J. Martin J.B. Replication of the neurochemical characteristics of HD using QA. Nature 1986 321 6066 168 171 10.1038/321168a0 2422561
    [Google Scholar]
  51. Sanberg P.R. Calderon S.F. Giordano M. Tew J.M. Norman A.B. The QA model of HD: Locomotor abnormalities. Exp. Neurol. 1989 105 1 45 53 10.1016/0014‑4886(89)90170‑2 2526022
    [Google Scholar]
  52. Tattersfield A.S. Croon R.J. Liu Y.W. Kells A.P. Faull R.L. Connor B. Neurogenesis in the striatum of the QA lesion model of HD. Neurosci 2004 127 2 319 332 10.1016/j.neuroscience.2004.04.061
    [Google Scholar]
  53. Beal M.F. Ferrante R.J. Swartz K.J. Kowall N.W. Chronic QA lesions in rats closely resembles HD. J. Neurosci. 1991 11 6 1649 1659 10.1523/JNEUROSCI.11‑06‑01649.1991 1710657
    [Google Scholar]
  54. Sumathi T. Vedagiri A. Ramachandran S. Purushothaman B. QA-induced HD-like sign mitigated using potent free radical scavenger edaravone-a pilot study on neurobehavioral, biochemical, and histological approach in male wistar rats. J. Mol. Neurosci. 2018 66 3 322 341 10.1007/s12031‑018‑1168‑1 30284227
    [Google Scholar]
  55. Vazey E.M. Dottori M. Jamshidi P. Tomas D. Pera M.F. Horne M. Connor B. Comparison of transplant efficiency amongst spontaneously derived and noggin-primed person embryonic stem cell neural precursors in the QA rat model of HD. Cell Transplant. 2010 19 8 1055 1062 10.3727/096368910X494632 20350346
    [Google Scholar]
  56. Popoli P. Pezzola A. Domenici M.R. Sagratella S. Diana G. Caporali M.G. Behavioral and electrophysiological correlates of the QA rat model of HD in rats. Brain Res. Bull. 1994 35 4 329 335 10.1016/0361‑9230(94)90109‑0 7850482
    [Google Scholar]
  57. Hamilton B.F. Gould D.H. Nature and distribution of brain lesions in rats intoxicated with 3-nitropropionic acid: A type of hypoxic (energy deficient) brain damage. Acta Neuropathol. 1987 72 3 286 297 10.1007/BF00691103 3564909
    [Google Scholar]
  58. Brouillet E. Jacquard C. Bizat N. Blum D. 3-Nitropropionic acid: A mitochondrial toxin to uncover physiopathological mechanisms underlying striatal degeneration in HD. J. Neurochem. 2005 95 6 1521 1540 10.1111/j.1471‑4159.2005.03515.x 16300642
    [Google Scholar]
  59. Borlongan C.V. Koutouzis T.K. Sanberg P.R. 3-Nitropropionic acid animal model and Huntington’ s disease. Neurosci. Biobehav. Rev. 1997 21 3 289 293 10.1016/S0149‑7634(96)00027‑9 9168265
    [Google Scholar]
  60. Borlongan C.V. Koutouzis T.K. Freeman T.B. Cahill D.W. Sanberg P.R. Behavioral pathology induced using recurrenceed systemic injections of 3-nitropropionic acid mimics the motoric sign of HD. Brain Res. 1995 697 1-2 254 257 10.1016/0006‑8993(95)00901‑2 8593585
    [Google Scholar]
  61. Beal M.F. Brouillet E. Jenkins B.G. Ferrante R.J. Kowall N.W. Miller J.M. Storey E. Srivastava R. Rosen B.R. Hyman B.T. Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J. Neurosci. 1993 13 10 4181 4192 10.1523/JNEUROSCI.13‑10‑04181.1993 7692009
    [Google Scholar]
  62. Stavrovskaya A.V. Voronkov D.N. Yamshchikova N.G. Ol’shanskiy A.S. Khudoerkov R.M. Illarioshkin S.N. Experience of experimental modelling of HD. Hum. Physiol. 2016 42 898 04 10.1134/S0362119716080120
    [Google Scholar]
  63. Lee J.M. Shih A.Y. Murphy T.H. Johnson J.A. NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons. J. Biol. Chem. 2003 278 39 37948 37956 10.1074/jbc.M305204200 12842875
    [Google Scholar]
  64. Deshpande S.B. Fukuda A. Nishino H. 3-Nitropropionic acid increases the intracellular Ca2+ in cultured astrocytes by reverse operation of the Na+-Ca2+ exchanger. Exp. Neurol. 1997 145 1 38 45 10.1006/exnr.1997.6457 9184107
    [Google Scholar]
  65. Tunez I. Tasset I. Perez-De La Cruz V. Santamaria A. 3-Nitropropionic acid as a tool to study the mechanisms involved in HD: Past, present and future. Molecules 2010 15 2 878 16 10.3390/molecules15020878 20335954
    [Google Scholar]
  66. Page K.J. Meldrum A. Dunnett S.B. The 3-nitropropionic acid model of HD. Mitochondrial Inhibitors and Neurodegenerative Ailmentss. Contemporary Neuroscience. Totowa, NJ Persona Press 2000 141 156
    [Google Scholar]
  67. Mehan S. Monga V. Rani M. Dudi R. Ghimire K. Neuroprotective effect of solanesol against 3-nitropropionic acid-induced HD-like behavioral, biochemical, and cellular alterations: Restoration of coenzyme-Q10-mediated mitochondrial dysfunction. Indian J. Pharmacol. 2018 50 309 319 10.4103/ijp.IJP_11_18 30783323
    [Google Scholar]
  68. Vis J.C. Verbeek M.M. De Waal R.M. Ten Donkelaar H.J. Kremer H.P. 3-Nitropropionic acid induces a spectrum of HD-like neuropathology in rat striatum. Neuropathol. Appl. Neurobiol. 1999 25 6 513 521 10.1046/j.1365‑2990.1999.00212.x 10632901
    [Google Scholar]
  69. Andrew S.E. Goldberg Y.P. Kremer B. Telenius H. Theilmann J. Adam S. Starr E. Squitieri F. Lin B. Kalchman M.A. Graham R.K. Hayden M.R. The relationship amongst trinucleotide (CAG) recurrences length and clinical features of HD. Nat. Genet. 1993 4 4 398 03 10.1038/ng0893‑398 8401589
    [Google Scholar]
  70. Hahn-Barma V. Deweer B. Durr A. Dode C. Feingold J. Pillon B. Agid Y. Brice A. Dubois B. Are cognitive changes the first sign of HD? A study of gene carriers. J. Neurol. Neurosurg. Psychiatry 1998 64 2 172 177 10.1136/jnnp.64.2.172 9489526
    [Google Scholar]
  71. Yang SH Cheng PH Banta H Towards a transgenic model of HD in a non-person primate. Nature 2008 453 7197 921 924 10.1038/nature06975 18488016
    [Google Scholar]
  72. Yang D. Wang C-E. Zhao B. Li W. Zhen O. Liu Z. Expression of HD protein results in apoptotic neurons in the brains of cloned transgenic pigs. Hum. Mol. Genet. 2010 19 20 3983 3994 10.1093/hmg/ddq313 20660116
    [Google Scholar]
  73. Jacobsen J.C. Bawden C.S. Rudiger S.R. McLaughlan C.J. Reid S.J. Waldvogel H.J. An ovine transgenic HD model. Hum. Mol. Genet. 2010 19 10 1873 1882 10.1093/hmg/ddq063 20154343
    [Google Scholar]
  74. Jiang A. Handley R.R. Lehnert K. Snell R.G. From pathogenesis to therapeutics: A review of 150 years of huntington’s disease research. Int. J. Mol. Sci. 2023 24 16 13021 10.3390/ijms241613021 37629202
    [Google Scholar]
  75. Kim A. Lalonde K. Truesdell A. Gomes Welter P. Brocardo P.S. Rosenstock T.R. Gil-Mohapel J. New avenues for the treatment of huntington’s disease. Int. J. Mol. Sci. 2021 22 16 8363 10.3390/ijms22168363 34445070
    [Google Scholar]
  76. Ojalvo-Pacheco J. Yakhine-Diop S.M.S. Fuentes J.M. Paredes-Barquero M. Niso-Santano M. Role of TFEB in huntington’s disease. Biology 2024 13 4 238 10.3390/biology13040238 38666850
    [Google Scholar]
  77. Jurcau A. Molecular pathophysiological mechanisms in huntington’s disease. Biomedicines 2022 10 6 1432 10.3390/biomedicines10061432 35740453
    [Google Scholar]
  78. Snyder B.R. Chan A.W.S. Progress in developing transgenic monkey model for Huntington’s disease. J. Neural Transm. 2018 125 3 401 417 10.1007/s00702‑017‑1803‑y 29127484
    [Google Scholar]
  79. Monk R. Connor B. Cell reprogramming to model huntington’s disease: A comprehensive review. Cells 2021 10 7 1565 10.3390/cells10071565 34206228
    [Google Scholar]
  80. Cepeda C. Levine M.S. Synaptic dysfunction in huntington’s disease: Lessons from genetic animal models. Neuroscientist 2022 28 1 20 40 10.1177/1073858420972662 33198566
    [Google Scholar]
  81. Han B. Liang W. Li X.J. Li S. Yan S. Tu Z. Large animal models for Huntington’s disease research. Zool. Res. 2024 45 2 275 283 10.24272/j.issn.2095‑8137.2023.199 38485497
    [Google Scholar]
  82. Li X.J. Lai L. A booming field of large animal model research. Zool. Res. 2024 45 2 311 313 10.24272/j.issn.2095‑8137.2024.018 38485501
    [Google Scholar]
  83. Kaye J. Reisine T. Finkbeiner S. Huntington’s disease mouse models: Unraveling the pathology caused by CAG repeat expansion. Fac. Rev. 2021 10 77 10.12703/r/10‑77 34746930
    [Google Scholar]
  84. Gubert C. Choo J.M. Love C.J. Kodikara S. Masson B.A. Liew J.J.M. Wang Y. Kong G. Narayana V.K. Renoir T. Lê Cao K.A. Rogers G.B. Hannan A.J. Faecal microbiota transplant ameliorates gut dysbiosis and cognitive deficits in Huntington’s disease mice. Brain Commun. 2022 4 4 fcac205 10.1093/braincomms/fcac205 36035436
    [Google Scholar]
  85. Morton A.J. Sleep and circadian rhythm dysfunction in animal models of huntington’s disease. J. Huntingtons Dis. 2023 12 2 133 148 10.3233/JHD‑230574 37334613
    [Google Scholar]
  86. Neto J.L. Lee J.M. Afridi A. Gillis T. Guide J.R. Dempsey S. Lager B. Alonso I. Wheeler V.C. Pinto R.M. Genetic contributors to intergenerational cag repeat instability in huntington’s disease knock-in mice. Genetics 2017 205 2 503 516 10.1534/genetics.116.195578 27913616
    [Google Scholar]
  87. Song H. Li H. Guo S. Pan Y. Fu Y. Zhou Z. Li Z. Wen X. Sun X. He B. Gu H. Zhao Q. Wang C. An P. Luo S. Hu Y. Xie X. Lu B. Targeting Gpr52 lowers mutant HTT levels and rescues Huntington’s disease-associated phenotypes. Brain 2018 141 6 1782 1798 10.1093/brain/awy081 29608652
    [Google Scholar]
  88. Franich N.R. Hickey M.A. Zhu C. Osborne G.F. Ali N. Chu T. Bove N.H. Lemesre V. Lerner R.P. Zeitlin S.O. Howland D. Neueder A. Landles C. Bates G.P. Chesselet M.F. Phenotype onset in Huntington’s disease knock-in mice is correlated with the incomplete splicing of the mutant huntingtin gene. J. Neurosci. Res. 2019 97 12 1590 1605 10.1002/jnr.24493 31282030
    [Google Scholar]
  89. Ravalia A.S. Lau J. Barron J.C. Purchase S.L.M. Southwell A.L. Hayden M.R. Nafar F. Parsons M.P. Super-resolution imaging reveals extrastriatal synaptic dysfunction in presymptomatic Huntington disease mice. Neurobiol. Dis. 2021 152 105293 10.1016/j.nbd.2021.105293 33556538
    [Google Scholar]
  90. Zarate N. Gundry K. Yu D. Casby J. Eberly L.E. Öz G. Gomez-Pastor R. Neurochemical correlates of synapse density in a Huntington’s disease mouse model. J. Neurochem. 2023 164 2 226 241 10.1111/jnc.15714 36272099
    [Google Scholar]
  91. Tkáč I. Xie T. Shah N. Larson S. Dubinsky J.M. Gomez-Pastor R. McLoughlin H.S. Orr H.T. Eberly L.E. Öz G. Regional sex differences in neurochemical profiles of healthy mice measured by magnetic resonance spectroscopy at 9.4 tesla. Front. Neurosci. 2023 17 1278828 10.3389/fnins.2023.1278828 37954878
    [Google Scholar]
  92. Estevez-Fraga C. Altmann A. Parker C.S. Scahill R.I. Costa B. Chen Z. Manzoni C. Zarkali A. Durr A. Roos R.A.C. Landwehrmeyer B. Leavitt B.R. Rees G. Tabrizi S.J. McColgan P. Genetic topography and cortical cell loss in Huntington’s disease link development and neurodegeneration. Brain 2023 146 11 4532 4546 10.1093/brain/awad275 37587097
    [Google Scholar]
  93. Ferguson M.W. Kennedy C.J. Palpagama T.H. Waldvogel H.J. Faull R.L.M. Kwakowsky A. Current and possible future therapeutic options for huntington’s disease. J. Cent. Nerv. Syst. Dis. 2022 14 11795735221092517 10.1177/11795735221092517 35615642
    [Google Scholar]
  94. Gosset P. Maxan A. Alpaugh M. Breger L. Dehay B. Tao Z. Ling Z. Qin C. Cisbani G. Fortin N. Vonsattel J.P.G. Lacroix S. Oueslati A. Bezard E. Cicchetti F. Evidence for the spread of human-derived mutant huntingtin protein in mice and non-human primates. Neurobiol. Dis. 2020 141 104941 10.1016/j.nbd.2020.104941 32422281
    [Google Scholar]
  95. Neueder A. Kojer K. Hering T. Lavery D.J. Chen J. Birth N. Hallitsch J. Trautmann S. Parker J. Flower M. Sethi H. Haider S. Lee J.M. Tabrizi S.J. Orth M. Abnormal molecular signatures of inflammation, energy metabolism, and vesicle biology in human Huntington disease peripheral tissues. Genome Biol. 2022 23 1 189 10.1186/s13059‑022‑02752‑5 36071529
    [Google Scholar]
  96. Jurcau A. Jurcau M.C. Therapeutic strategies in huntington’s disease: From genetic defect to gene therapy. Biomedicines 2022 10 8 1895 10.3390/biomedicines10081895 36009443
    [Google Scholar]
  97. Dickey A.S. La Spada A.R. Therapy development in Huntington disease: From current strategies to emerging opportunities. Am. J. Med. Genet. A. 2018 176 4 842 861 10.1002/ajmg.a.38494 29218782
    [Google Scholar]
  98. Tong H. Yang T. Xu S. Li X. Liu L. Zhou G. Yang S. Yin S. Li X.J. Li S. Huntington’s disease: Complex pathogenesis and therapeutic strategies. Int. J. Mol. Sci. 2024 25 7 3845 10.3390/ijms25073845 38612657
    [Google Scholar]
  99. Chia K. Klingseisen A. Sieger D. Priller J. Zebrafish as a model organism for neurodegenerative disease. Front. Mol. Neurosci. 2022 15 940484 10.3389/fnmol.2022.940484 36311026
    [Google Scholar]
  100. Wilton D.K. Stevens B. The contribution of glial cells to Huntington’s disease pathogenesis. Neurobiol. Dis. 2020 143 104963 10.1016/j.nbd.2020.104963 32593752
    [Google Scholar]
  101. Vaz R.L. Outeiro T.F. Ferreira J.J. Zebrafish as an animal model for drug discovery in parkinson’s disease and other movement disorders: A systematic review. Front. Neurol. 2018 9 347 10.3389/fneur.2018.00347 29910763
    [Google Scholar]
  102. Nittari G. Roy P. Martinelli I. Bellitto V. Tomassoni D. Traini E. Tayebati S. Amenta F. Rodent models of huntington’s disease: An overview. Biomedicines 2023 11 12 3331 10.3390/biomedicines11123331 38137552
    [Google Scholar]
  103. Wang J. Cao H. Zebrafish and medaka: Important animal models for human neurodegenerative diseases. Int. J. Mol. Sci. 2021 22 19 10766 10.3390/ijms221910766 34639106
    [Google Scholar]
  104. Bondulich M.K. Phillips J. Cañibano-Pico M. Nita I.M. Byrne L.M. Wild E.J. Bates G.P. Translatable plasma and CSF biomarkers for use in mouse models of Huntington’s disease. Brain Commun. 2023 6 1 fcae030 10.1093/braincomms/fcae030 38370446
    [Google Scholar]
  105. Scahill R.I. Zeun P. Osborne-Crowley K. Johnson E.B. Gregory S. Parker C. Lowe J. Nair A. O’Callaghan C. Langley C. Papoutsi M. McColgan P. Estevez-Fraga C. Fayer K. Wellington H. Rodrigues F.B. Byrne L.M. Heselgrave A. Hyare H. Sampaio C. Zetterberg H. Zhang H. Wild E.J. Rees G. Robbins T.W. Sahakian B.J. Langbehn D. Tabrizi S.J. Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington’s disease Young Adult Study (HD-YAS): A cross-sectional analysis. Lancet Neurol. 2020 19 6 502 512 10.1016/S1474‑4422(20)30143‑5 32470422
    [Google Scholar]
/content/journals/rrct/10.2174/0115748871372165250625212002
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The Role of Animal Models in Huntington's Disease Clinical Trials: Decoding Genetic, Non-Genetic, and Molecular Pathways
Bentham Science Publishers ; https://doi.org/10.2174/0115748871372165250625212002
/content/journals/rrct/10.2174/0115748871372165250625212002
/content/journals/rrct/10.2174/0115748871372165250625212002
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  • Article Type:     Review Article
Keywords: central nervous system ; neurodegenerative disorder ; molecular pathways ; genetic models ; KI model ; genetic pathways ; non-genetic pathways ; Huntington disorder ; clinical trials ; HD gene ; animal

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