, Volume 2, Issue 3, pp 471–479

Animal models of Kennedy disease



Since the identification of the polyglutamine repeat expansion responsible for Kennedy disease (KD) more than a decade ago, several laboratories have created animal models for KD. The slowly progressive nature of KD, its X-linked dominant mode of inheritance, and its recently elucidated hormone dependence have made the modeling of this lower motor neuron disease uniquely challenging. Several models have been generated in which variations in specificity, age of onset, and rate of progression have been achieved. Animal models that precisely reproduce the motor neuron specificity, delayed onset, and slow progression of disease may not support preclinical therapeutics testing, whereas models with rapidly progressing symptoms may preclude the ability to fully elucidate pathogenic pathways. Drosophila models of KD provide unique opportunities to use the power of genetics to identify pathogenic pathways at work in KD. This paper reviews the new wealth of transgenic mouse and Drosophila models for KD. Whereas differences, primarily in neuropathological findings, exist in these models, these differences may be exploited to begin to elucidate the most relevant pathological features of KD.

Key Words

Kennedy disease polyglutamine spinal and bulbar muscular atrophy androgen receptor 


  1. 1.
    Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset: a sex-linked recessive trait. Neurology 18: 671–680, 1968.PubMedGoogle Scholar
  2. 2.
    Sobue G, Hashizume Y, Mukai E, Hirayama M, Mitsuma T, Takahashi A. X-linked recessive bulbospinal neronopathy: a clinicopathological study. Brain 112: 209–232, 1989.PubMedCrossRefGoogle Scholar
  3. 3.
    Li M, Miwa S, Kobayashi Y, Merry DE, Yamamoto M, Tanaka F, et al. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol 44: 249–254, 1998.PubMedCrossRefGoogle Scholar
  4. 4.
    Li M, Nakagomi Y, Kobayashi Y, Merry DE, Tanaka F, Doyu M, et al. Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy. Am J Pathol 153: 695–701, 1998.PubMedCrossRefGoogle Scholar
  5. 5.
    Adachi H, Katsuno M, Minamiyama M, Waza M, Sang C, Nakagomi Y, et al. Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain 57: 236–251, 2005.Google Scholar
  6. 6.
    Ferlini A, Patrosso MC, Guidetti D, Merlini L, Uncini A, Ragno M, et al. Androgen receptor gene (CAG)n repeat analysis in the differential diagnosis between Kennedy disease and other motoneuron disorders. Am J Med Genet 55: 105–111, 1995.PubMedCrossRefGoogle Scholar
  7. 7.
    Fischbeck KH, Ionasescu V, Ritter AW, Ionasescu R, Davies K, Ball S, et al. Localization of the gene for X-linked spinal muscular atrophy. Neurology 36: 1595–1598, 1986.PubMedGoogle Scholar
  8. 8.
    Migeon BR, Brown TR, Axelman J, Migeon CJ. Studies of the locus for androgen receptor: localization on the human X chromosome and evidence for homology with the Tfm locus in the mouse. Proc Natl Acad Sci USA 78: 6339–6343, 1981.PubMedCrossRefGoogle Scholar
  9. 9.
    La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 353: 77–79, 1991.CrossRefGoogle Scholar
  10. 10.
    La Spada AR, Roling D, Harding AE, Warner CL, Speigel R, Hausmanowa-Petrusewicz I, et al. Meiotic stability and genotype-phenotype correlation of the expanded trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nat Genet 2: 301–304, 1992.PubMedCrossRefGoogle Scholar
  11. 11.
    Zoghbi HY, Oit HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci 23: 217–247, 2000.PubMedCrossRefGoogle Scholar
  12. 12.
    Bingham PM, Scott MO, Wang S, McPhaul MJ, Wilson EM, Garbem JY, et al. Stability of an expanded trinucleotide repeat in the androgen receptor gene in transgenic mice. Nat Genet 9: 191–196, 1995.PubMedCrossRefGoogle Scholar
  13. 13.
    Merry DE, McCampbell A, Taye AA, Winston RL, Fischbeck KH. Toward a mouse model for spinal and bulbar muscular atrophy: effect of neuronal expression of androgen receptor in transgenic mice. Am J Hum Genet 59 [Suppl]: A271, 1996.Google Scholar
  14. 14.
    La Spada AR, Peterson KR, Meadows SA, McClain ME, Jeng G, Chmelar RS, et al. Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability. Hum Mol Genet 7: 959–967, 1998.PubMedCrossRefGoogle Scholar
  15. 15.
    Ikeda H, Yamaguchi M, Sugai S, Aze Y, Naruiya S, Kakizuka A. Expanded polygluatmine in the Machado-Joseph disease protein induces cell death in vitro and in vivo. Nat Genet 13: 196–202, 1996.PubMedCrossRefGoogle Scholar
  16. 16.
    Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, et al. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19: 1–20, 1997.CrossRefGoogle Scholar
  17. 17.
    Merry DE, Kobayashi Y, Bailey CK, Taye AA, Fischbeck KH. Cleavage, aggregation and toxicity of the expanded androgen receptor in spinal and bulbar muscular atrophy. Hum Mol Genet 7: 693–701, 1998.PubMedCrossRefGoogle Scholar
  18. 18.
    Brooks BP, Paulson HL, Merry DE, Salazar-Grueso EF, Brinkmann AO, Wilson EM, et al. Characterization of an expanded glutamine repeat androgen receptor in a neuronal cell culture system. Neurobiol Dis 4: 313–323, 1997.CrossRefGoogle Scholar
  19. 19.
    Diamond MI, Robinson MR, Yamamoto KR. Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor. Proc Natl Acad Sci USA 97: 657–661, 2000.PubMedCrossRefGoogle Scholar
  20. 20.
    Abel A, Walcott J, Woods J, Duda J, Merry DE. Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. Hum Mol Genet 10: 107–116, 2001.PubMedCrossRefGoogle Scholar
  21. 21.
    Adachi H, Kume A, Li M, Nakagomi Y, Niwa H, Do J, et al. Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death. Hum Mol Genet 10: 1039–1048, 2001.PubMedCrossRefGoogle Scholar
  22. 22.
    McManamny P, Chy HS, Finkelstein DI, Craythom RG, Crack PJ, Kola I, et al. A mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 11: 2103–2111, 2002.PubMedCrossRefGoogle Scholar
  23. 23.
    Katsuno M, Adachi H, Kume A, Li M, Nakagomi Y, Niwa H, et al. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35: 843–854, 2002.PubMedCrossRefGoogle Scholar
  24. 24.
    Sopher BL, Thomas PS Jr, LaFevre-Bemt MA, Holm IE, Wilke SA, Ware CB, et al. Androgen receptor YAC transgenic mice recapitulate SB MA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 41: 687–699, 2004.PubMedCrossRefGoogle Scholar
  25. 25.
    Chevalier-Larsen ES, O’Brien CJ, Wang H, Jenkins SC, Holder L, Lieberman AP, et al. Castration restores function and neurofilament alterations of aged symptomatic males in a transgenic mouse model of spinal and bulbar muscular atrophy. J Neurosci 24: 4778–4786, 2004.PubMedCrossRefGoogle Scholar
  26. 26.
    Zhou Z-x, Lane MV, Kamppainen JA, French FS, Wilson EM. Specificity of ligand-dependent androgen receptor stabilization: receptor domain interactions influence ligand dissociation and receptor stability. Mol Endocrinol 9: 208–218, 1995.PubMedCrossRefGoogle Scholar
  27. 27.
    Nucifora JFC, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, et al. Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science 291: 2423–2428, 2001.PubMedCrossRefGoogle Scholar
  28. 28.
    Dunah AW, Jeong H, Griffin A, Kim YM, Standaert DG, Hersch SM, et al. Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science 296: 2238–2243, 2002.PubMedCrossRefGoogle Scholar
  29. 29.
    McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, et al. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9: 2197–2202, 2000.PubMedCrossRefGoogle Scholar
  30. 30.
    McCampbell A, Taye AA, Whitty L, Penney E, Steffan JS, Fischbeck KH. Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc Natl Acad Sci USA 98: 15179–15184, 2001.PubMedCrossRefGoogle Scholar
  31. 31.
    Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413: 739–743, 2001.PubMedCrossRefGoogle Scholar
  32. 32.
    Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Natl Acad Sci USA 100: 2041–2046, 2003.PubMedCrossRefGoogle Scholar
  33. 33.
    Jiang H, Nucifora FC Jr, Ross CA, DeFranco DB. Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein. Hum Mol Genet 12: 1–12, 2003.PubMedCrossRefGoogle Scholar
  34. 34.
    Carrero P, Okamoto K, Coumailleau P, O’Brien S, Tanaka H, Poellinger L. Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1 α, Mol Cell Biol 20: 402–415, 2000.PubMedCrossRefGoogle Scholar
  35. 35.
    Dames SA, Martinez-Yamout M, de Guzman RN, Dyson HJ, Wright PE. Structural basis for Hif-1 α/CBP recognition in the cellular hypoxic response. Proc Natl Acad Sci USA 99: 5271–5276, 2002.PubMedCrossRefGoogle Scholar
  36. 36.
    Freedman SJ, Sun ZY, Poy F, Kung AL, Livingston DM, Wagner G, et al. Structural basis for recruitment of CBP/p300 by hypoxiainducible factor-1α. Proc Natl Acad Sci USA 99: 5367–5372, 2002.PubMedCrossRefGoogle Scholar
  37. 37.
    Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor prmoter causes motor neuron degeneration. Nat Genet 28: 131–138, 2001.PubMedCrossRefGoogle Scholar
  38. 38.
    Saudou F, Finkbeiner S, Devys D, Greenberg ME. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95: 55–66, 1998.PubMedCrossRefGoogle Scholar
  39. 39.
    Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, et al. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95: 41–53, 1998.PubMedCrossRefGoogle Scholar
  40. 39a.
    Simeoni S, Mancini MA, Stenoien DL, Marcelli M, Weigel NL, Zanisi M, Martini L, Poletti A. Motoneuronal cell death is not correlated with aggregate formation of androgen receptors containing an elongated polyglutamine tract. Hum Mol Genet 9: 133–144, 2000.PubMedCrossRefGoogle Scholar
  41. 40.
    Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431: 805–810, 2004.PubMedCrossRefGoogle Scholar
  42. 41.
    Wacker JL, Zareie MH, Fong H, Sarikaya M, Muchowski PJ. Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nat Struct Mol Biol 11: 1215–1222, 2004.PubMedCrossRefGoogle Scholar
  43. 42.
    Hirano A, Donnenfeld H, Sasaki S, Nakano I. Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 43: 461–470, 1984.PubMedCrossRefGoogle Scholar
  44. 43.
    Holzbaur ELF. Motor neurons rely on motor proteins. Trends Cell Biol 14: 233–240, 2004.PubMedCrossRefGoogle Scholar
  45. 44.
    Chan HY, Warrick JM, Andriola I, Merry D, Bonini NM. Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet 11: 2895–2904, 2002.PubMedCrossRefGoogle Scholar
  46. 45.
    Takeyama K, Ito S, Yamamoto A, Tanimoto H, Furutani T, Kanuka H, et al. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 35: 855–864, 2002.PubMedCrossRefGoogle Scholar
  47. 46.
    Walcott JL, Merry DE. Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy. J Biol Chem 277: 50855–50859, 2002.PubMedCrossRefGoogle Scholar
  48. 47.
    Katsuno M, Adachi H, Doyu M, Minamiyama M, Sang C, Kobayashi Y, et al. Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. Nat Med 9: 768–773, 2003.PubMedCrossRefGoogle Scholar
  49. 48.
    Pozzi P, Bendotti C, Simeoni S, Piccioni F, Guerini V, Manon TU, et al. Androgen 5-α-reductase type 2 is highly expressed and active in rat spinal cord motor neurones. J Neuroendocrinol 15: 882–887, 2003.PubMedCrossRefGoogle Scholar
  50. 49.
    Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM, et al. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429: 413–417, 2004.PubMedCrossRefGoogle Scholar
  51. 50.
    Szebenyi G, Morfini GA, Babcock A, Gould M, Selkoe K, Stenoien DL, et al. Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40: 41–52, 2003.PubMedCrossRefGoogle Scholar
  52. 51.
    Piccioni F, Pinton P, Simeoni S, Pozzi P, Fascio U, Vismara G, et al. Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motor neuronal processes. FASEB J 16: 1418–1420, 2002.PubMedGoogle Scholar
  53. 52.
    Gunawardena S, Her L-S, Brusch RG, Laymon RA, Niesman IR, Gordesky-Gold B, et al. Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40: 25–40, 2003.PubMedCrossRefGoogle Scholar
  54. 53.
    Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, et al. Mutant dynactin in motor neuron disease. Nat Genet 33: 455–456, 2003.PubMedCrossRefGoogle Scholar
  55. 54.
    Hafezparast M, Klocke R, Ruhrberg C, Marquardt A, Ahmad-Annuar A, Bowen S, et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300: 808–812, 2003.PubMedCrossRefGoogle Scholar
  56. 55.
    LaMonte BH, Wallace KE, Holloway BA, Shelly SS, Ascano J, Tokito M, et al. Disruption of dynein/dynactin inhibits axonal transport in motor neurons causing late-onset progressive degeneration. Neuron 34: 715–727, 2002.PubMedCrossRefGoogle Scholar
  57. 56.
    Minamiyama M, Katsuno M, Adachi H, Waza M, Sang C, Kobayashi Y, et al. Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 13: 1183–1192, 2004.PubMedCrossRefGoogle Scholar
  58. 57.
    Adachi H, Katsuno M, Minamiyama M, Sang C, Pagoulatos G, Angelidis C, et al. Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein. J Neurosci 23: 2203–2211, 2003.PubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc 2005

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular PharmacologyThomas Jefferson UniversityPhiladelphia

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