Advertisement

Animal Models of Machado-Joseph Disease

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1049)

Abstract

Animal models are an important tool to study the pathophysiology of Machado-Joseph Disease (MJD). So far, animal models using simple organisms (like the round worm Caenorhabditis elegans or the fruit fly drosophila) but also mammalian models (mouse and even a non-human primate model) have been generated to study MJD. While simple organisms made an important contribution to the identification of pathophysiological mechanisms in MJD and were further used for modifier and screening purposes, mammalian models recapitulate major disease features of MJD in humans and are therefore a highly valuable tool for e.g. the validation of mechanisms or for pre-clinical validation of treatment approaches. Here we give an overview about the strategies which were used to model MJD and about the different models generated so far. We further highlight advantages of specific model organisms and describe the new findings which were made employing these animal models of MJD.

Keywords

Animal models Drosophila C. elegans Mus musculus Transgenic 

References

  1. 1.
    Matos CA, de Macedo-Ribeiro S, Carvalho AL (2011) Polyglutamine diseases: the special case of ataxin-3 and Machado-Joseph disease. Prog Neurobiol 95(1):26–48CrossRefGoogle Scholar
  2. 2.
    Bessa C, Maciel P, Rodrigues AJ (2013) Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders. Mol Neurobiol 48(3):465–489CrossRefGoogle Scholar
  3. 3.
    Sonnhammer EL, Durbin R (1997) Analysis of protein domain families in Caenorhabditis elegans. Genomics 46(2):200–216CrossRefGoogle Scholar
  4. 4.
    Rodrigues AJ, Coppola G, Santos C, Costa Mdo C, Ailion M, Sequeiros J, Geschwind DH, Maciel P (2007) Functional genomics and biochemical characterization of the C. elegans orthologue of the Machado-Joseph disease protein ataxin-3. FASEB J 21(4):1126–1136CrossRefGoogle Scholar
  5. 5.
    Rodrigues AJ, Neves-Carvalho A, Ferro A, Rokka A, Corthals G, Logarinho E, Maciel P (2009) ATX-3, CDC-48 and UBXN-5: a new trimolecular complex in Caenorhabditis elegans. Biochem Biophys Res Commun 386(4):575–581CrossRefGoogle Scholar
  6. 6.
    Rodrigues AJ, Neves-Carvalho A, Teixeira-Castro A, Rokka A, Corthals G, Logarinho E, Maciel P (2011) Absence of ataxin-3 leads to enhanced stress response in C. elegans. PLoS One 6(4):e18512CrossRefGoogle Scholar
  7. 7.
    Khan LA, Bauer PO, Miyazaki H, Lindenberg KS, Landwehrmeyer BG, Nukina N (2006) Expanded polyglutamines impair synaptic transmission and ubiquitin-proteasome system in Caenorhabditis elegans. J Neurochem 98(2):576–587CrossRefGoogle Scholar
  8. 8.
    Teixeira-Castro A, Ailion M, Jalles A, Brignull HR, Vilaça JL, Dias N, Rodrigues P, Oliveira JF, Neves-Carvalho A, Morimoto RI, Maciel P (2011) Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: rescue by the DAF-16 and HSF-1 pathways. Hum Mol Genet 20(15):2996–3009CrossRefGoogle Scholar
  9. 9.
    Christie NT, Lee AL, Fay HG, Gray AA, Kikis EA (2014) Novel polyglutamine model uncouples proteotoxicity from aging. PLoS One 9(5):e96835CrossRefGoogle Scholar
  10. 10.
    Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I, Kimura J, Narumiya S, Kakizuka A (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8(3):221–228CrossRefGoogle Scholar
  11. 11.
    Goto J, Watanabe M, Ichikawa Y, Yee SB, Ihara N, Endo K, Igarashi S, Takiyama Y, Gaspar C, Maciel P, Tsuji S, Rouleau GA, Kanazawa I (1997) Machado-Joseph disease gene products carrying different carboxyl termini. Neurosci Res 28(4):373–377CrossRefGoogle Scholar
  12. 12.
    Ikeda H, Yamaguchi M, Sugai S, Aze Y, Narumiya S, Kakizuka A (1996) Expanded polyglutamine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet 13(2):196–202CrossRefGoogle Scholar
  13. 13.
    Teixeira-Castro A, Jalles A, Esteves S, Kang S, da Silva Santos L, Silva-Fernandes A, Neto MF, Brielmann RM, Bessa C, Duarte-Silva S, Miranda A, Oliveira S, Neves-Carvalho A, Bessa J, Summavielle T, Silverman RB, Oliveira P, Morimoto RI, Maciel P (2015) Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease. Brain 138(Pt 11):3221–3237CrossRefGoogle Scholar
  14. 14.
    Bier E (2005) Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet 6:9–23CrossRefGoogle Scholar
  15. 15.
    Warrick JM, Paulson HL, Gray-Board GL, Bui QT, Fischbeck KH, Pittman RN, Bonini NM (1998) Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93(6):939–949CrossRefGoogle Scholar
  16. 16.
    Warrick JM, Morabito LM, Bilen J, Gordesky-Gold B, Faust LZ, Paulson HL, Bonini NM (2005) Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol Cell 18(1):37–48CrossRefGoogle Scholar
  17. 17.
    Jung J, Bonini N (2007) CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease. Science 315(5820):1857–1859CrossRefGoogle Scholar
  18. 18.
    Kretzschmar D, Tschäpe J, Bettencourt Da Cruz A, Asan E, Poeck B, Strauss R, Pflugfelder GO (2005) Glial and neuronal expression of polyglutamine proteins induce behavioral changes and aggregate formation in Drosophila. Glia 49(1):59–72CrossRefGoogle Scholar
  19. 19.
    Jung J, Xu K, Lessing D, Bonini NM (2009) Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3. Hum Mol Genet 18(24):4843–4852CrossRefGoogle Scholar
  20. 20.
    Chan HY, Warrick JM, Gray-Board GL, Paulson HL, Bonini NM (2000) Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum Mol Genet 9(19):2811–2820CrossRefGoogle Scholar
  21. 21.
    Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 23(4):425–428CrossRefGoogle Scholar
  22. 22.
    Bilen J, Bonini NM (2007) Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila. PLoS Genet 3(10):1950–1964CrossRefGoogle Scholar
  23. 23.
    Voßfeldt H, Butzlaff M, PrüSSing K, Ní Chárthaigh RA, Karsten P, Lankes A, Hamm S, Simons M, Adryan B, Schulz JB, Voigt A (2012) Large-scale screen for modifiers of ataxin-3-derived polyglutamine-induced toxicity in Drosophila. PLoS One 7(11):e47452CrossRefGoogle Scholar
  24. 24.
    Li LB, Yu Z, Teng X, Bonini NM (2008) RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453(7198):1107–1111CrossRefGoogle Scholar
  25. 25.
    Lessing D, Bonini NM (2008) Polyglutamine genes interact to modulate the severity and progression of neurodegeneration in Drosophila. PLoS Biol 6(2):e29CrossRefGoogle Scholar
  26. 26.
    Schmitt I, Linden M, Khazneh H, Evert BO, Breuer P, Klockgether T, Wuellner U (2007) Inactivation of the mouse Atxn3 (ataxin-3) gene increases protein ubiquitination. Biochem Biophys Res Commun 362(3):734–739CrossRefGoogle Scholar
  27. 27.
    Switonski PM, Fiszer A, Kazmierska K, Kurpisz M, Krzyzosiak WJ, Figiel M (2011) Mouse ataxin-3 functional knock-out model. Neuromolecular Med 13(1):54–65CrossRefGoogle Scholar
  28. 28.
    Cemal CK, Carroll CJ, Lawrence L, Lowrie MB, Ruddle P, Al-Mahdawi S, King RH, Pook MA, Huxley C, Chamberlain S (2002) YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit. Hum Mol Genet 11(9):1075–1094CrossRefGoogle Scholar
  29. 29.
    Chen X, Tang TS, Tu H, Nelson O, Pook M, Hammer R, Nukina N, Bezprozvanny I (2008) Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3. J Neurosci 28(48):12713–12724CrossRefGoogle Scholar
  30. 30.
    Rodríguez-Lebrón E, Costa MD, Luna-Cancalon K, Peron TM, Fischer S, Boudreau RL, Davidson BL, Paulson HL (2013) Silencing mutant ATXN3 expression resolves molecular phenotypes in SCA3 transgenic mice. Mol Ther 21(10):1909–1918CrossRefGoogle Scholar
  31. 31.
    Shakkottai VG, do Carmo Costa M, Dell’Orco JM, Sankaranarayanan A, Wulff H, Paulson HL (2011) Early changes in cerebellar physiology accompany motor dysfunction in the polyglutamine disease spinocerebellar ataxia type 3. J Neurosci 31(36):13002–13014CrossRefGoogle Scholar
  32. 32.
    Goti D, Katzen SM, Mez J, Kurtis N, Kiluk J, Ben-Haïem L, Jenkins NA, Copeland NG, Kakizuka A, Sharp AH, Ross CA, Mouton PR, Colomer V (2004) A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J Neurosci 24(45):10266–10279CrossRefGoogle Scholar
  33. 33.
    Colomer Gould VF, Goti D, Pearce D, Gonzalez GA, Gao H, Bermudez de Leon M, Jenkins NA, Copeland NG, Ross CA, Brown DR (2007) A mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice. Neurobiol Dis 27(3):362–369CrossRefGoogle Scholar
  34. 34.
    Bichelmeier U, Schmidt T, Hübener J, Boy J, Rüttiger L, Häbig K, Poths S, Bonin M, Knipper M, Schmidt WJ, Wilbertz J, Wolburg H, Laccone F, Riess O (2007) Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. J Neurosci 27(28):7418–7428CrossRefGoogle Scholar
  35. 35.
    Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC (2010) Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133(Pt 1):93–104CrossRefGoogle Scholar
  36. 36.
    Chou AH, Yeh TH, Ouyang P, Chen YL, Chen SY, Wang HL (2008) Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. Neurobiol Dis 31(1):89–101CrossRefGoogle Scholar
  37. 37.
    Chou AH, Chen SY, Yeh TH, Weng YH, Wang HL (2011) HDAC inhibitor sodium butyrate reverses transcriptional downregulation and ameliorates ataxic symptoms in a transgenic mouse model of SCA3. Neurobiol Dis 41(2):481–488CrossRefGoogle Scholar
  38. 38.
    Chou AH, Lin AC, Hong KY, Hu SH, Chen YL, Chen JY, Wang HL (2011) p53 activation mediates polyglutamine-expanded ataxin-3 upregulation of Bax expression in cerebellar and pontine nuclei neurons. Neurochem Int 58(2):145–152CrossRefGoogle Scholar
  39. 39.
    Chou AH, Chen YL, Hu SH, Chang YM, Wang HL (2014) Polyglutamine-expanded ataxin-3 impairs long-term depression in Purkinje neurons of SCA3 transgenic mouse by inhibiting HAT and impairing histone acetylation. Brain Res 1583:220–229CrossRefGoogle Scholar
  40. 40.
    Chou AH, Chen YL, Chiu CC, Yuan SJ, Weng YH, Yeh TH, Lin YL, Fang JM, Wang HL (2015) T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse. Neuropharmacology 99:308–317CrossRefGoogle Scholar
  41. 41.
    Wang HL, Hu SH, Chou AH, Wang SS, Weng YH, Yeh TH (2013) H1152 promotes the degradation of polyglutamine-expanded ataxin-3 or ataxin-7 independently of its ROCK-inhibiting effect and ameliorates mutant ataxin-3-induced neurodegeneration in the SCA3 transgenic mouse. Neuropharmacology 70:1–11CrossRefGoogle Scholar
  42. 42.
    Duarte-Neves J, Gonçalves N, Cunha-Santos J, Simões AT, den Dunnen WF, Hirai H, Kügler S, Cavadas C, Pereira de Almeida L (2015) Neuropeptide Y mitigates neuropathology and motor deficits in mouse models of Machado-Joseph disease. Hum Mol Genet 24(19):5451–5463CrossRefGoogle Scholar
  43. 43.
    Konno A, Shuvaev AN, Miyake N, Miyake K, Iizuka A, Matsuura S, Huda F, Nakamura K, Yanagi S, Shimada T, Hirai H (2014) Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar Purkinje cells. Cerebellum 13(1):29–41CrossRefGoogle Scholar
  44. 44.
    Nóbrega C, Nascimento-Ferreira I, Onofre I, Albuquerque D, Hirai H, Déglon N, de Almeida LP (2013) Silencing mutant ataxin-3 rescues motor deficits and neuropathology in Machado-Joseph disease transgenic mice. PLoS One 8(1):e52396CrossRefGoogle Scholar
  45. 45.
    Torashima T, Koyama C, Iizuka A, Mitsumura K, Takayama K, Yanagi S, Oue M, Yamaguchi H, Hirai H (2008) Lentivector-mediated rescue from cerebellar ataxia in a mouse model of spinocerebellar ataxia. EMBO Rep 9(4):393–399CrossRefGoogle Scholar
  46. 46.
    Schmidt J, Schmidt T, Golla M, Lehmann L, Weber JJ, Hübener-Schmid J, Riess O (2016) In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3. J Neurochem 138(1):150–162CrossRefGoogle Scholar
  47. 47.
    Boy J, Schmidt T, Wolburg H, Mack A, Nuber S, Böttcher M, Schmitt I, Holzmann C, Zimmermann F, Servadio A, Riess O (2009) Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3. Hum Mol Genet 18(22):4282–4295CrossRefGoogle Scholar
  48. 48.
    Boy J, Schmidt T, Schumann U, Grasshoff U, Unser S, Holzmann C, Schmitt I, Karl T, Laccone F, Wolburg H, Ibrahim S, Riess O (2010) A transgenic mouse model of spinocerebellar ataxia type 3 resembling late disease onset and gender-specific instability of CAG repeats. Neurobiol Dis 37(2):284–293CrossRefGoogle Scholar
  49. 49.
    Silva-Fernandes A, Costa Mdo C, Duarte-Silva S, Oliveira P, Botelho CM, Martins L, Mariz JA, Ferreira T, Ribeiro F, Correia-Neves M, Costa C, Maciel P (2010) Motor uncoordination and neuropathology in a transgenic mouse model of Machado-Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products. Neurobiol Dis 40(1):163–176CrossRefGoogle Scholar
  50. 50.
    Duarte-Silva S, Neves-Carvalho A, Soares-Cunha C, Teixeira-Castro A, Oliveira P, Silva-Fernandes A, Maciel P (2014) Lithium chloride therapy fails to improve motor function in a transgenic mouse model of Machado-Joseph disease. Cerebellum 13(6):713–727CrossRefGoogle Scholar
  51. 51.
    Duarte-Silva S, Silva-Fernandes A, Neves-Carvalho A, Soares-Cunha C, Teixeira-Castro A, Maciel P (2016) Combined therapy with m-TOR-dependent and -independent autophagy inducers causes neurotoxicity in a mouse model of Machado-Joseph disease. Neuroscience 313:162–173CrossRefGoogle Scholar
  52. 52.
    Esteves S, Duarte-Silva S, Naia L, Neves-Carvalho A, Teixeira-Castro A, Rego AC, Silva-Fernandes A, Maciel P (2015) Limited effect of chronic valproic acid treatment in a mouse model of Machado-Joseph Disease. PLoS One 10(10):e0141610CrossRefGoogle Scholar
  53. 53.
    Silva-Fernandes A, Duarte-Silva S, Neves-Carvalho A, Amorim M, Soares-Cunha C, Oliveira P, Thirstrup K, Teixeira-Castro A, Maciel P (2014) Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease. Neurotherapeutics 11(2):433–449CrossRefGoogle Scholar
  54. 54.
    Hübener J, Vauti F, Funke C, Wolburg H, Ye Y, Schmidt T, Wolburg-Buchholz K, Schmitt I, Gardyan A, Driessen S, Arnold HH, Nguyen HP, Riess O (2011) N-terminal ataxin-3 causes neurological symptoms with inclusions, endoplasmic reticulum stress and ribosomal dislocation. Brain 134(Pt 7):1925–1942CrossRefGoogle Scholar
  55. 55.
    Switonski PM, Szlachcic WJ, Krzyzosiak WJ, Figiel M (2015) A new humanized ataxin-3 knock-in mouse model combines the genetic features, pathogenesis of neurons and glia and late disease onset of SCA3/MJD. Neurobiol Dis 73:174–188CrossRefGoogle Scholar
  56. 56.
    Ramani B, Harris GM, Huang R, Seki T, Murphy GG, Costa Mdo C, Fischer S, Saunders TL, Xia G, McEachin RC, Paulson HL (2015) A knockin mouse model of spinocerebellar ataxia type 3 exhibits prominent aggregate pathology and aberrant splicing of the disease gene transcript. Hum Mol Genet 24(5):1211–1224CrossRefGoogle Scholar
  57. 57.
    Harris GM, Dodelzon K, Gong L, Gonzalez-Alegre P, Paulson HL (2010) Splice isoforms of the polyglutamine disease protein ataxin-3 exhibit similar enzymatic yet different aggregation properties. PLoS One 5(10):e13695CrossRefGoogle Scholar
  58. 58.
    Colomer Gould VF, Goti D, Kiluk J (2006) A neuroendocrine dysfunction, not testicular mutant ataxin-3 cleavage fragment or aggregate, causes cell death in testes of transgenic mice. Cell Death Differ 13(3):524–526CrossRefGoogle Scholar
  59. 59.
    Williams AJ, Knutson TM, Colomer Gould VF, Paulson HL (2009) In vivo suppression of polyglutamine neurotoxicity by C-terminus of Hsp70-interacting protein (CHIP) supports an aggregation model of pathogenesis. Neurobiol Dis 33(3):342–353CrossRefGoogle Scholar
  60. 60.
    Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A 89(12):5547–5551CrossRefGoogle Scholar
  61. 61.
    Kazachkova N, Raposo M, Montiel R, Cymbron T, Bettencourt C, Silva-Fernandes A, Silva S, Maciel P, Lima M (2013) Patterns of mitochondrial DNA damage in blood and brain tissues of a transgenic mouse model of Machado-Joseph disease. Neurodegener Dis 11(4):206–214CrossRefGoogle Scholar
  62. 62.
    Ramos A, Kazachkova N, Silva F, Maciel P, Silva-Fernandes A, Duarte-Silva S, Santos C, Lima M (2015) Differential mtDNA damage patterns in a transgenic mouse model of Machado-Joseph disease (MJD/SCA3). J Mol Neurosci 55(2):449–453CrossRefGoogle Scholar
  63. 63.
    Alves S, Régulier E, Nascimento-Ferreira I, Hassig R, Dufour N, Koeppen A, Carvalho AL, Simões S, de Lima MC, Brouillet E, Gould VC, Déglon N, de Almeida LP (2008) Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease. Hum Mol Genet 17(14):2071–2083CrossRefGoogle Scholar
  64. 64.
    Alves S, Nascimento-Ferreira I, Auregan G, Hassig R, Dufour N, Brouillet E, Pedroso de Lima MC, Hantraye P, Pereira de Almeida L, Déglon N (2008) Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease. PLoS One 3(10):e3341CrossRefGoogle Scholar
  65. 65.
    Alves S, Nascimento-Ferreira I, Dufour N, Hassig R, Auregan G, Nóbrega C, Brouillet E, Hantraye P, Pedroso de Lima MC, Déglon N, de Almeida LP (2010) Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: no role for wild-type ataxin-3? Hum Mol Genet 19(12):2380–2394CrossRefGoogle Scholar
  66. 66.
    Nóbrega C, Nascimento-Ferreira I, Onofre I, Albuquerque D, Conceição M, Déglon N, de Almeida LP (2013) Overexpression of mutant ataxin-3 in mouse cerebellum induces ataxia and cerebellar neuropathology. Cerebellum 12(4):441–455CrossRefGoogle Scholar
  67. 67.
    Tomioka I, Ishibashi H, Minakawa EN, Motohashi HH, Takayama O, Saito Y, Popiel HA, Puentes S, Owari K, Nakatani T, Nogami N, Yamamoto K, Noguchi S, Yonekawa T, Tanaka Y, Fujita N, Suzuki H, Kikuchi H, Aizawa S, Nagano S, Yamada D, Nishino I, Ichinohe N, Wada K, Kohsaka S, Nagai Y, Seki K (2017) Transgenic monkey model of the polyglutamine diseases recapitulating progressive neurological symptoms. eNeuro 4(2). pii: ENEURO.0250-16.2017CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of Medical Genetics and Applied Genomics, University of TuebingenTuebingenGermany

Personalised recommendations