Skip to main content

Molecular Pathogenesis in Huntington’s Disease


Huntington’s disease (HD) is a severe autosomal dominant neurodegenerative disorder characterized by a combination of motor, cognitive, and psychiatric symptoms, atrophy of the basal ganglia and the cerebral cortex, and inevitably progressive course resulting in death 5–20 years after manifestation of its symptoms. HD is caused by expansion of CAG repeats in the HTT gene, which leads to pathological elongation of the polyglutamine tract within the respective protein-huntingtin. In this review, we present a modern view on molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. Main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as systemic failure of transcription, mitochondrial dysfunction and suppression of energy metabolism, abnormalities of cytoskeleton and axonal transport, microglial inflammation, decrease in synthesis of brain-derived neurotrophic factor, etc.

This is a preview of subscription content, access via your institution.



brain-derived neurotrophic factor


central nervous system


Huntington’s disease


peroxisome proliferator-activated receptor γ coactivator 1α


  1. 1.

    Baig, S. S., Strong, M., and Quarrell, O. W. (2016) The global prevalence of Huntington’s disease: a systematic review and discussion, Neurodegener. Dis. Manag., 6, 331–343.

    Article  PubMed  Google Scholar 

  2. 2.

    Hayden, M. R. (1981) Huntington’s Chorea, Springer-Verlag, Berlin.

    Book  Google Scholar 

  3. 3.

    Bates, G. P., Dorsey, R., Gusella, J. F., Hayden, M. R., Kay, C., Leavitt, B. R., Nance, M., Ross, C. A., Scahill, R. I., Wetzel, R., Wild, E. J., and Tabrizi, S. J. (2015) Huntington’s disease, Nature Rev. Dis. Primers, 1, 1–21.

    Google Scholar 

  4. 4.

    The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes, Cell, 72, 971–983.

  5. 5.

    Paulson, H. L. (1999) Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis)fold, Am. J. Hum. Genet., 64, 339–345.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. 6.

    Wheeler, V. C., Persichetti, F., McNeil, S. M., Mysore, J. S., Mysore, S. S., MacDonald, M. E., Myers, R. H., Gusella, J. F., Wexler, N. S., and The US-Venezuela Collaborative Research Group (2007) Factors associated with HD CAG repeat instability in Huntington’s disease, J. Med. Gen., 44, 695–701.

    Article  CAS  Google Scholar 

  7. 7.

    Reiner, A., Dragatsis, I., and Dietrich, P. (2011) Genetics and neuropathology of Huntington’s disease, Int. Rev. Neurobiol., 98, 325–372.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. 8.

    Duyao, M., Ambrose, C., Myers, R., Novelletto, A., Persichetti, F., Frontali, M., Folstein, S., Ross, C., Franz, M., Abbott, M., Gray, J., Conneally, P., Young, A., Penney, J., Hollingsworth, Z., Shoulson, I., Lazzarini, A., Falek, A., Koroshetz, W., Sax, D., Bird, E., Vonsattel, J., Bonilla, E., Alvir, J., Bickham Conde, J., Cha, J.-H., Dure, L., Gomez, F., Ramos, M., Sanchez-Ramos, J., Snodgrass, S., de Young, M., Wexler, N., Moscowitz, C., Penchaszadeh, G., MacFarlane, H., Anderson, M., Jenkins, B., Srinidhi, J., Barnes, G., Gusella, J., and MacDonald, M. (1993) Trinucleotide repeat length instability and age of onset in Huntington’s disease, Nat. Genet., 4, 387–392.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Andresen, J. M., Javiar, G., Djousse, L., Roberts, S., Brocklebank, D., Cherny, S. S., The US-Venezuela Collaborative Research Group, HD MAPS Collaborative Research Group, Cardon, L. R., Gusella, J. F., MacDonald, M. E., Myers, R. H., Housman, D. E., and Wexler, N. S. (2006) The relationship between CAG repeat length and age of onset differs for Huntington’s disease patients with juvenile onset or adult onset, Hum. Gen., 71, 295–301.

    Article  CAS  Google Scholar 

  10. 10.

    Brinkman, R. R., Mezei, M. M., Theilmann, J., Almqvist, E., and Hayden, M. R. (1997) The likelihood of being affected with Huntington’s disease by a particular age, for a specific CAG size, Am. J. Hum. Genet., 60, 1202–1210.

    PubMed  PubMed Central  CAS  Google Scholar 

  11. 11.

    Persichetti, F., Srinidhi, J., Kanaley, L., Ge, P., Myers, R. H., D’Arrigo, K., Barnes, G. T., MacDonald, M. E., Vonsattel, J. P., Gusella, J. F., and Bird, E. D. (1994) Huntington’s disease CAG trinucleotide repeats in pathologically confirmed post-mortem brains, Neurobiol. Dis., 1, 159–166.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Illarioshkin, S. N., Igarashi, S., Onodera, O., Markova, E. D., Nikolskaya, N. N., Tanaka, H., Chabrashwili, T. Z., Insarova, N. G., Endo, K., Ivanova-Smolenskaya, I. A., and Tsuji, S. (1994) Trinucleotide repeat length and rate of progression of Huntington’s disease, Ann. Neurol., 36, 630–635.

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Brandt, J., Bylsma, F. W., Gross, R., Stine, O. C., Ranen, N., and Ross, C. A. (1996) Trinucleotide repeat length and clinical progression in Huntington’s disease, Neurology, 46, 527–531.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Rosenblatt, A., Liang, K. Y., Zhou, H., Abbott, M. H., Gourley, L. M., Margolis, R. L., Brandt, J., and Ross, C. A. (2006) The association of CAG repeat length with clinical progression in Huntington’s disease, Neurology, 66, 1016–1020.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Myers, R. H. (2004) Huntington’s disease genetics, NeuroRx, 1, 255–262.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Tautz, D., and Schlotterer, C. (1994) Simple sequences, Curr. Opin. Genet. Dev., 4, 832–837.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Klintschar, M., Dauber, E.-M., Ricci, U., Cerri, N., Immel, U. D., Kleiber, M., and Mayr, W. R. (2004) Haplotype studies support slippage as the mechanism of germline mutations in short tandem repeats, Electrophoresis, 25, 3344–3348.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Zuccato, C., and Cattaneo, E. (2016) The Huntington’s paradox, Sci. Am., 315, 56–61.

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Saudou, F., and Humbert, S. (2016) The biology of huntingtin, Neuron, 89, 910–926.

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Velier, J., Kim, M., Schwarz, C., Kim, T. W., Sapp, E., Chase, K., Aronin, N., and DiFiglia, M. (1998) Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways, Exp. Neurol., 152, 34–40.

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Nithianantharajah, J., and Hannan, A. J. (2013) Dysregulation of synaptic proteins, dendritic spine abnormalities and pathological plasticity of synapses as experience-dependent mediators of cognitive and psychiatric symptoms in Huntington’s disease, Neuroscience, 251, 66–74.

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Martin, D. D. O., Ladha, S., Ehrnhoefer, D. E., and Hayden, M. R. (2014) Autophagy in Huntington’s disease and huntingtin in autophagy, Trends Neurosci., 38, 26–35.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Perutz, M. F., Johnson, T., Suzuki, M., and Finch, J. T. (1994) Glutamine repeats as polar zippers: their possible role in inherited neurologic diseases, Proc. Natl. Acad. Sci. USA, 91, 5355–5358.

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Landles, C., Sathasivam, K., Weiss, A., Woodman, B., Moffitt, H., Finkbeiner, S., Sun, B., Gafni, J., Ellerby, L. M., Trottier, Y., Richards, W. G., Osmand, A., Paganetti, P., and Bates, G. P. (2010) Proteolysis of mutant huntingtin produces an exon 1 fragment that accumulates as an aggregated protein in neuronal nuclei in Huntington’s disease, J. Biol. Chem., 285, 8808–8823.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. 25.

    Rubinsztein, D. C., Wyttenbach, A., and Rankin, J. (1999) Intracellular inclusions, pathological markers in diseases caused by expanded polyglutamine tracts? J. Med. Genet., 36, 265–270.

    PubMed  PubMed Central  CAS  Google Scholar 

  26. 26.

    Ross, C. A., Wood, J. D., and Schilling, G. (1999) Polyglutamine pathogenesis, Philos. Trans. R. Soc. Lond. B Biol. Sci., 354, 1005–1011.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 27.

    Graham, R. K., Deng, Y., and Slow, E. J. (2006) Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin, Cell, 125, 1179–1191.

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Saudou, F., Finkbeiner, S., Devys, D., and Greenberg, M. E. (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions, Cell, 95, 55–66.

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Klement, I. A., Skinner, P. A., Kaytor, M. D., Yi, H., Hersch, S. M., Clark, H. B., Zoghbi, H. Y., and Orr, H. T. (1998) Ataxin-1 nuclear localisation and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice, Cell, 95, 41–53.

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    DiFiglia, M., Sapp, E., Chase, K. O., Davies, S. W., Bates, G. P., Vonsattel, J. P., and Aronin, N. (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain, Science, 277, 1990–1993.

    Article  PubMed  CAS  Google Scholar 

  31. 31.

    Scherzinger, E., Lurz, R., Turmaine, M., Mangiarini, L., Hollenbach, B., Hasenbank, R., Bates, G. P., Davies, S. W., Lehrach, H., and Wanker, E. E. (1997) Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo, Cell, 90, 549–558.

    Article  PubMed  CAS  Google Scholar 

  32. 32.

    Davies, S. W., Turmaine, M., Cozens, B. A., DiFiglia, M., Sharp, A. H., Ross, C. A., Scherzinger, E., Wanker, E. E., Mangiarini, L., and Bates, G. P. (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation, Cell, 90, 537–548.

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Warrick, J. M., Paulson, H. L., Gray-Board, G. L., Bui, Q. T., Fischbeck, K. H., Pittman, R. N., and Bonini, N. M. (1998) Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila, Cell, 93, 939–949.

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Nekrasov, E. D., Vigont, V. A., Klyushnikov, S. A., Lebedeva, O. S., Vassina, E. M., Bogomazova, A. N., Chestkov, I. V., Semashko, T. A., Kiseleva, E., Suldina, L. A., Bobrovsky, P. A., Zimina, O. A., Ryazantseva, M. A., Skopin, A. Y., Illarioshkin, S. N., Kaznacheyeva, E. V., Lagarkova, M. A., and Kiselev, S. L. (2016) Manifestation of Huntington’s disease pathology in human induced pluripotent stem cell-derived neurons, Mol. Neurodegener., 11,27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. 35.

    Kalchman, M. A., Graham, R. K., Xia, G., Koide, H. B., Hodgson, J. G., Graham, K. C., Goldberg, Y. P., Gietz, R. D., Pickart, C. M., and Hayden, M. R. (1996) Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme, J. Biol. Chem., 271, 19385–19394.

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Chai, Y., Koppenhafer, S. L., Shoesmith, S. J., Perez, M. K., and Paulson, H. L. (1999) Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of poly-glutamine aggregation in vitro, Hum. Mol. Genet., 8, 673–682.

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Holmberg, C. I., Staniszewski, K. E., Mensah, K. N., Matouschek, A., and Morimoto, R. I. (2004) Inefficient degradation of truncated polyglutamine proteins by the proteasome, EMBO J., 23, 4307–4318.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Labbadia, J., and Morimoto, R. I. (2013) Huntington’s disease: underlying molecular mechanisms and emerging concepts, Trends Biochem. Sci., 38, 378–385.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. 39.

    Zhao, T., Hong, Y., Li, X.-J., and Li, S.-H. (2016) Subcellular clearance and accumulation of Huntington’s disease protein: a mini-review, Front. Mol. Neurosci., 9,27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. 40.

    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., and Rubinsztein, D. C. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington’s disease, Nat. Genet., 36, 585–595.

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Ravikumar, B., Acevedo-Arozena, A., Imarisio, S., Berger, Z., Vacher, C., O’Kane, C. J., Brown, S. D., and Rubinsztein, D. C. (2005) Dynein mutations impair autophagic clearance of aggregate-prone proteins, Nat. Genet., 37, 771–776.

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Harding, R. J., and Tong, Y. F. (2018) Proteostasis in Huntington’s disease: disease mechanisms and therapeutic opportunities, Acta Pharmacol. Sin., 39, 754–769.

    Article  PubMed  CAS  Google Scholar 

  43. 43.

    Kim, M., Lee, H.-S., LaForet, G., McIntyre, C., Martin, E. J., Chang, P., Kim, T. W., Williams, M., Reddy, P. H., Tagle, D., Boyce, F. M., Won, L., Heller, A., Aronin, N., and DiFiglia, M. (1999) Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition, J. Neurosci., 19, 964–973.

    Article  PubMed  CAS  Google Scholar 

  44. 44.

    Cummings, C. J., Reinstein, E., Sun, Y., Antalffy, B., Jiang, Y., Ciechanover, A., Orr, H. T., Beaudet, A. L., and Zoghbi, H. Y. (1999) Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequency while accelerating polyglutamine-induced pathology in SCA1 mice, Neuron, 24, 879–892.

    Article  PubMed  CAS  Google Scholar 

  45. 45.

    Valor, L. M. (2015) Transcription, epigenetics and ameliorative strategies in Huntington’s disease: a genome-wide perspective, Mol. Neurobiol., 51, 406–423.

    Article  PubMed  CAS  Google Scholar 

  46. 46.

    La Spada, A. R., Weydt, P., and Pineda, V. V. (2011) Huntington’s disease pathogenesis: mechanisms and path-ways, in Neurobiology of Huntington’s Disease: Applications to Drug Discovery (Lo, D. C., and Hughes, R. E., eds.), Chap. 2, Taylor & Francis, Boca Raton.

    Google Scholar 

  47. 47.

    Cong, S. Y., Pepers, B. A., Evert, B. O., Rubinsztein, D. C., Roos, R. A., van Ommen, G. J., and Dorsman, J. C. (2005) Mutant huntingtin represses CBP, but not p300, by binding and protein degradation, Mol. Cell. Neurosci., 30, 560–571.

    Article  PubMed  CAS  Google Scholar 

  48. 48.

    Qiu, Z., Norflus, F., Singh, B., Swindell, M. K., Buzescu, R., Bejarano, M., Chopra, R., Zucker, B., Benn, C. L., DiRocco, D. P., Cha, J. H., Ferrante, R. J., and Hersch, S. M. (2006) Sp1 is up-regulated in cellular and transgenic models of Huntington’s disease, and its reduction is neuroprotective, J. Biol. Chem., 281, 16672–16680.

    Article  PubMed  CAS  Google Scholar 

  49. 49.

    Futter, M., Diekmann, H., Schoenmakers, E., Sadiq, O., Chatterjee, K., and Rubinsztein, D. C. (2009) Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors, J. Med. Genet., 46, 438–446.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. 50.

    Zuccato, C., and Cattaneo, E. (2007) Role of brain-derived neurotrophic factor in Huntington’s disease, Prog. Neurobiol., 81, 294–330.

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    Kelly, D. P., and Scarpulla, R. C. (2004) Transcriptional regulatory circuits controlling mitochondrial biogenesis and function, Genes Dev., 18, 357–368.

    Article  PubMed  CAS  Google Scholar 

  52. 52.

    Beal, M. F., Brouillet, E., Jenkins, B. G., Ferrante, R. J., Kowall, N. W., Miller, J. M., Storey, E., Srivastava, R., Rosen, B. R., and Hyman, B. T. (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid, J. Neurosci., 13, 4181–4189.

    Article  PubMed  CAS  Google Scholar 

  53. 53.

    Tabrizi, S. J., Cleeter, M. W., Xuereb, J., Taanman, J. W., Cooper, J. M., and Schapira, A. H. (1999) Biochemical abnormalities and excitotoxicity in Huntington’s disease brain, Ann. Neurol., 45, 25–32.

    Article  PubMed  CAS  Google Scholar 

  54. 54.

    Johri, A., Chandra, A., and Beal, M. F. (2013) PGC-1a, mitochondrial dysfunction, and Huntington’s disease, Free Radic. Biol. Med., 62, 37–46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. 55.

    Harms, L., Meierkord, H., Timm, G., Pfeiffer, L., and Ludolph, A. C. (1997) Decreased N-acetylaspartate/choline ratio and increased lactate in the frontal lobe of patients with Huntington’s disease: a proton magnetic resonance spectroscopy study, J. Neurol. Neurosurg. Psychiatry, 62, 27–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. 56.

    Reddy, P. H., and Shirendeb, U. P. (2012) Mutant huntingtin, abnormal mitochondrial dynamics, defective axonal transport of mitochondria, and selective synaptic degeneration in Huntington’s disease, Biochim. Biophys. Acta, 1822, 101–110.

    Article  PubMed  CAS  Google Scholar 

  57. 57.

    Orr, A. L., Li, S., Wang, C. E., Li, H., Wang, J., Rong, J., Xu, X., Mastroberardino, P. G., Greenamyre, J. T., and Li, X. J. (2008) N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking, J. Neurosci., 28, 2783–2792.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. 58.

    Twig, G., and Shirihai, O. S. (2011) The interplay between mitochondrial dynamics and mitophagy, Antioxid. Redox Signal., 14, 1939–1951.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. 59.

    Martinez-Vicente, M., Talloczy, Z., Wong, E., Tang, G., Koga, H., Kaushik, S., de Vries, R., Arias, E., Harris, S., Sulzer, D., and Cuervo, A. M. (2010) Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease, Nat. Neurosci., 13, 567–576.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. 60.

    Puigserver, P., and Spiegelman, B. M. (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator, Endocr. Rev., 24, 78–90.

    Article  PubMed  CAS  Google Scholar 

  61. 61.

    Lin, J., Wu, P. H., Tarr, P. T., Lindenberg, K. S., St.-Pierre, J., Zhang, C. Y., Mootha, V. K., Jager, S., Vianna, C. R., Reznick, R. M., Cui, L., Manieri, M., Donovan, M. X., Wu, Z., Cooper, M. P., Fan, M. C., Rohas, L. M., Zavacki, A. M., Cinti, S., Shulman, G. I., Lowell, B. B., Krainc, D., and Spiegelman, B. M. (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice, Cell, 119, 121–123.

    Article  PubMed  CAS  Google Scholar 

  62. 62.

    Leone, T. C., Lehman, J. J., and Finck, B. N. (2005) PGC-1alpha deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis, PLoS Biol., 3, e101.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. 63.

    Gunawardena, S., and Goldstein, L. S. (2005) Polyglutamine diseases and transport problems: deadly traffic jams on neuronal highways, Arch. Neurol., 62, 46–51.

    Article  PubMed  Google Scholar 

  64. 64.

    Zala, D., Hinckelmann, M. V., Yu, H., Lyra da Cunha, M. M., Liot, G., Cordelieres, F. P., Marco, S., and Saudou, F. (2013) Vesicular glycolysis provides on-board energy for fast axonal transport, Cell, 152, 479–491.

    Article  PubMed  CAS  Google Scholar 

  65. 65.

    Gauthier, L. R., Charrin, B. C., Borrell-Pages, M., Dompierre, J. P., Rangone, H., Cordelieres, F. P., De Mey, J., MacDonald, M. E., Lessmann, V., Humbert, S., and Saudou, F. (2004) Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules, Cell, 118, 127–138.

    Article  PubMed  CAS  Google Scholar 

  66. 66.

    Trushina, E., Dyer, R. B., Badger, J. D., Ure, D., Eide, L., Tran, D. D., Vrieze, B. T., Legendre-Guillemin, V., McPherson, P. S., Mandavilli, B. S., Van Houten, B., Zeitlin, S., McNiven, M., Aebersold, R., Hayden, M., Parisi, J. E., Seeberg, E., Dragatsis, I., Doyle, K., Bender, A., Chacko, C., and McMurray, C. T. (2004) Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro, Mol. Cell. Biol., 24, 8195–8209.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. 67.

    Crotti, A., and Glass, C. K. (2015) The choreography of neuroinflammation in Huntington’s disease, Trends Immunol., 36, 364–373.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. 68.

    Nimmerjahn, A., Kirchhoff, F., and Helmchen, F. (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo, Science, 308, 1314–1318.

    Article  PubMed  CAS  Google Scholar 

  69. 69.

    Banati, R. B. (2002) Visualizing microglial activation in vivo, Glia, 40, 206–217.

    Article  PubMed  Google Scholar 

  70. 70.

    Sapp, E., Kegel, K. B., Aronin, N., Hashikawa, T., Uchiyama, Y., Tohyama, K., Bhide, P. G., Vonsattel, J. P., and DiFiglia, M. (2001) Early and progressive accumulation of reactive microglia in the Huntington’s disease brain, J. Neuropathol. Exp. Neurol., 60, 161–172.

    Article  PubMed  CAS  Google Scholar 

  71. 71.

    Tai, Y. F., Pavese, N., Gerhard, A., Tabrizi, S. J., Barker, R. A., Brooks, D. J., and Piccini, P. (2007) Microglial activation in presymptomatic Huntington’s disease gene carriers, Brain, 130, 1759–1766.

    Article  PubMed  Google Scholar 

  72. 72.

    Crotti, A., Benner, C., Kerman, B. E., Lagier-Tourenne, C., Zuccato, C., Cattaneo, E., Gage, F. H., Cleveland, D. W., and Glass, C. K. (2014) Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors, Nat. Neurosci., 4, 513–521.

    Article  CAS  Google Scholar 

  73. 73.

    Kumar, A., and Ratan, R. R. (2016) Oxidative stress and Huntington’s disease: the good, the bad, and the ugly, J. Huntington’s Dis., 5, 217–237.

    Article  Google Scholar 

  74. 74.

    Hands, S., Sajjad, M. U., Newton, M. J., and Wyttenbach, A. (2011) In vitro and in vivo aggregation of a fragment of huntingtin protein directly causes free radical production, J. Biol. Chem., 286, 44512–44520.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. 75.

    Block, M. L., Zecca, L., and Hong, J. S. (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms, Nat. Rev. Neurosci., 8, 57–69.

    Article  PubMed  CAS  Google Scholar 

  76. 76.

    Firdaus, W. J., Wyttenbach, A., Giuliano, P., Kretz-Remy, C., Currie, R. W., and Arrigo, A. P. (2006) Huntingtin inclusion bodies are iron-dependent centers of oxidative events, FEBS J., 273, 5428–5441.

    Article  PubMed  CAS  Google Scholar 

  77. 77.

    Hodgson, J. G., Agopyan, N., Gutekunst, C.-A., Leavitt, B. R., LePiane, F., Singaraja, R., Smith, D. J., Bissada, N., McCutcheon, K., Nasir, J., Jamot, L., Li, X. J., Stevens, M. E., Rosemond, E., Roder, J. C., Phillips, A. G., Rubin, E. M., Hersch, S. M., and Hayden, M. R. (1999) A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration, Neuron, 23, 181–192.

    Article  PubMed  CAS  Google Scholar 

  78. 78.

    Skotte, N. H., Andersen, J. V., Santos, A., Aldana, B. I., Willert, C. W., Norremolle, A., Waagepetersen, H. S., and Nielsen, M. L. (2018) Integrative characterization of the R6/2 mouse model of Huntington’s disease reveals dysfunctional astrocyte metabolism, Cell Rep., 23, 2211–2224.

    Article  PubMed  CAS  Google Scholar 

  79. 79.

    Lievens, J. C., Rival, T., Iche, M., Chneiweiss, H., and Birman, S. (2005) Expanded polyglutamine peptides disrupt EGF receptor signaling and glutamate transporter expression in Drosophila, Hum. Mol. Genet., 14, 713–724.

    Article  PubMed  CAS  Google Scholar 

  80. 80.

    Canals, J. M., Pineda, J. R., Torres-Peraza, J. F., Bosch, M., Martin-Ibanez, R., Munoz, M. T., Mengod, G., Ernfors, P., and Alberch, J. (2004) Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington’s disease, J. Neurosci., 24, 7727–7739.

    Article  PubMed  CAS  Google Scholar 

  81. 81.

    Strand, A. D., Baquet, Z. C., Aragaki, A. K., Holmans, P., Yang, L., Cleren, C., Beal, M. F., Jones, L., Kooperberg, C., Olson, J. M., and Jones, K. R. (2007) Expression profiling of Huntington’s disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration, J. Neurosci., 27, 11758–11768.

    Article  PubMed  CAS  Google Scholar 

  82. 82.

    Sanchez, I., Xu, C.-J., Juo, P., Kakizaka, A., Blenis, J., and Yuan, J. (1999) Caspase-8 is required for cell death induced by expanded polyglutamine repeats, Neuron, 22, 623–633.

    Article  PubMed  CAS  Google Scholar 

  83. 83.

    Dragatsis, I., Levine, M. S., and Zeitlin, S. (2000) Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice, Nat. Genet., 26, 300–306.

    Article  PubMed  CAS  Google Scholar 

  84. 84.

    Van Raamsdonk, J. M., Pearson, J., Rogers, D. A., Bissada, N., Vogl, A. W., Hayden, M. R., and Leavitt, B. R. (2005) Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington’s disease, Hum. Mol. Genet., 14, 1379–1392.

    Article  PubMed  CAS  Google Scholar 

  85. 85.

    Sun, Y., Savanenin, A., Reddy, P. H., and Liu, Y. F. (2001) Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-D-aspartate receptors via post-synaptic density 95, J. Biol. Chem., 276, 24713–24718.

    Article  PubMed  CAS  Google Scholar 

  86. 86.

    Francelle, L., Lotz, C., Outeiro, T., Brouillet, E., and Merienne, K. (2017) Contribution of neuroepigenetics to Huntington’s disease, Front. Hum. Neurosci., 11,17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. 87.

    Coarelli, G., Diallo, A., Thion, M. S., Rinaldi, D., Calvas, F., Boukbiza, O. L., Tataru, A., Charles, P., Tranchant, C., Marelli, C., Ewenczyk, C., Tchikviladze, M., Monin, M. L., Carlander, B., Anheim, M., Brice, A., Mochel, F., Tezenas du Montcel, S., Humbert, S., and Durr, A. (2017) Low cancer prevalence in polyglutamine expansion diseases, Neurology, 88, 1114–1119.

    Article  PubMed  CAS  Google Scholar 

  88. 88.

    Sorensen, S. A., Fenger, K., and Olsen, J. H. (1999) Significantly lower incidence of cancer among patients with Huntington’s disease: an apoptotic effect of an expanded polyglutamine tract? Cancer, 86, 1342–1346.

    Article  PubMed  CAS  Google Scholar 

  89. 89.

    Mestre, T. A., and Sampaio, C. (2017) Huntington’s disease: linking pathogenesis to the development of experimental therapeutics, Curr. Neurol. Neurosci. Rep., 17, 18.

    Article  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to S. N. Illarioshkin.

Additional information

Original Russian Text © S. N. Illarioshkin, S. A. Klyushnikov, V. A. Vigont, Yu. A. Seliverstov, E. V. Kaznacheyeva, 2018, published in Biokhimiya, 2018, Vol. 83, No. 9, pp. 1299–1310.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Illarioshkin, S.N., Klyushnikov, S.A., Vigont, V.A. et al. Molecular Pathogenesis in Huntington’s Disease. Biochemistry Moscow 83, 1030–1039 (2018).

Download citation


  • Huntington’s disease
  • molecular pathogenesis
  • polyglutamine expansion
  • proteolytic stress
  • transcription dysregulation
  • mitochondria