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Cell and Tissue Research

, Volume 349, Issue 1, pp 313–320 | Cite as

Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy (SBMA)

  • Haruhiko Banno
  • Masahisa Katsuno
  • Keisuke Suzuki
  • Fumiaki TanakaEmail author
  • Gen SobueEmail author
Review

Abstract

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is an adult-onset, X-linked motor neuron disease characterized by muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. SBMA is caused by the expansion of a CAG triplet repeat, encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The histopathological finding in SBMA is the loss of lower motor neurons in the anterior horn of the spinal cord as well as in the brainstem motor nuclei. There is no established disease-modifying therapy for SBMA. Animal studies have revealed that the pathogenesis of SBMA depends on the level of serum testosterone, and that androgen deprivation mitigates neurodegeneration through inhibition of nuclear accumulation and/or stabilization of the pathogenic AR. Heat shock proteins, the ubiquitin–proteasome system and transcriptional regulation are also potential targets for development of therapy for SBMA. Among these therapeutic approaches, the luteinizing hormone-releasing hormone analogue, leuprorelin, prevents nuclear translocation of aberrant AR proteins, resulting in a significant improvement of disease phenotype in a mouse model of SBMA. In a phase 2 clinical trial of leuprorelin, the patients treated with this drug exhibited decreased mutant AR accumulation in scrotal skin biopsy. Phase 3 clinical trial showed the possibility that leuprorelin treatment is associated with improved swallowing function particularly in patients with a disease duration less than 10 years. These observations suggest that pharmacological inhibition of the toxic accumulation of mutant AR is a potential therapy for SBMA.

Keywords

Spinal and bulbar muscular atrophy (SBMA) Polyglutamine disease Androgen receptor (AR) Leuprorelin Clinical trial 

References

  1. Adachi H, Katsuno M, Minamiyama M, Sang C, Pagoulatos G, Angelidis C, Kusakabe M, Yoshiki A, Kobayashi Y, Doyu M, Sobue G (2003) 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 23:2203–2211PubMedGoogle Scholar
  2. Adachi H, Katsuno M, Minamiyama M, Waza M, Sang C, Nakagomi Y, Kobayashi Y, Tanaka F, Doyu M, Inukai A, Yoshida M, Hashizume Y, Sobue G (2005) Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain 128:659–670PubMedCrossRefGoogle Scholar
  3. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death.Nature 431:805–810Google Scholar
  4. Atsuta N, Watanabe H, Ito M, Banno H, Suzuki K, Katsuno M, Tanaka F, Tamakoshi A, Sobue G (2006) Natural history of spinal and bulbar muscular atrophy (SBMA): A study of 223 Japanese patients. Brain 129:1446–1455PubMedCrossRefGoogle Scholar
  5. Banno H, Adachi H, Katsuno M, Suzuki K, Atsuta N, Watanabe H, Tanaka F, Doyu M, Sobue G (2006) Mutant androgen receptor accumulation in spinal and bulbar muscular atrophy scrotal skin: A pathogenic marker. Ann Neurol 59:520–526PubMedCrossRefGoogle Scholar
  6. Banno H, Katsuno M, Suzuki K, Takeuchi Y, Kawashima M, Suga N, Takamori M, Ito M, Nakamura T, Matsuo K, Yamada S, Oki Y, Adachi H, Minamiyama M, Waza M, Atsuta N, Watanabe H, Fujimoto Y, Nakashima T, Tanaka F, Doyu M, Sobue G (2009) Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Ann Neurol 65:140–150PubMedCrossRefGoogle Scholar
  7. Banno H, Katsuno M, Suzuki K, Sobue G (2011) Dutasteride for spinal and bulbar muscular atrophy. Lancet Neurol 10:113–115PubMedCrossRefGoogle Scholar
  8. Bates G (2003) Huntingtin aggregation and toxicity in Huntington's disease. Lancet 361:1642–1644PubMedCrossRefGoogle Scholar
  9. Borovecki F, Lovrecic L, Zhou J, Jeong H, Then F, Rosas HD, Hersch SM, Hogarth P, Bouzou B, Jensen RV, Krainc D (2005) Genome-wide expression profiling of human blood reveals biomarkers for Huntington's disease. Proc Natl Acad Sci USA 102:11023–11028PubMedCrossRefGoogle Scholar
  10. Chevalier-Larsen ES, O'Brien CJ, Wang HY, Jenkins SC, Holder L, Lieberman AP, Merry DE (2004) Castration restores function and neurofilament alterations of aged symptomatic males in a transgenic mouse model of spinal and bulbar muscular atrophy. J Neurosci 24:4778–4786PubMedCrossRefGoogle Scholar
  11. Doyu M, Sobue G, Mukai E, Kachi T, Yasuda T, Mitsuma T, Takahashi A (1992) Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG repeat in androgen receptor gene. Ann Neurol 32:707–710PubMedCrossRefGoogle Scholar
  12. Fernández-Rhodes LE, Kokkinis AD, White MJ, Watts CA, Auh S, Jeffries NO, Shrader JA, Lehky TJ, Li L, Ryder JE, Levy EW, Solomon BI, Harris-Love MO, La Pean A, Schindler AB, Chen C, Di Prospero NA, Fischbeck KH (2011) Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomized placebo-controlled trial. Lancet Neurol 10:140–147PubMedCrossRefGoogle Scholar
  13. Fischbeck KH (1997) Kennedy disease. J Inherit Metab Dis 20:152–158PubMedCrossRefGoogle Scholar
  14. Foradori CD, Weiser MJ, Handa RJ (2008) Non-genomic actions of androgens. Front Neuroendocrinol 29:169–181PubMedCrossRefGoogle Scholar
  15. Gatchel JR, Zoghbi HY (2005) Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 6:743–755PubMedCrossRefGoogle Scholar
  16. Guidetti D, Sabadini R, Ferlini A, Torrente I (2001) Epidemiological survey of X-linked bulbar and spinal muscular atrophy, or Kennedy disease, in the province of Reggio Emilia, Italy. Eur J Epidemiol 17:587–591PubMedCrossRefGoogle Scholar
  17. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12PubMedCrossRefGoogle Scholar
  18. Katsuno M, Adachi H, Kume A, Li M, Nakagomi Y, Niwa H, Sang C, Kobayashi Y, Doyu M, Sobue G (2002) Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35:843–854PubMedCrossRefGoogle Scholar
  19. Katsuno M, Adachi H, Doyu M, Minamiyama M, Sang C, Kobayashi Y, Inukai A, Sobue G (2003) Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. Nat Med 9:768–773PubMedCrossRefGoogle Scholar
  20. Katsuno M, Sang C, Adachi H, Minamiyama M, Waza M, Tanaka F, Doyu M, Sobue G (2005) Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease. Proc Natl Acad Sci USA 102:16801–16806PubMedCrossRefGoogle Scholar
  21. Katsuno M, Adachi H, Waza M, Banno H, Suzuki K, Tanaka F, Doyu M, Sobue G (2006a) Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA). Exp Neurol 200:8–18PubMedCrossRefGoogle Scholar
  22. Katsuno M, Adachi H, Minamiyama M, Waza M, Tokui K, Banno H, Suzuki K, Onoda Y, Tanaka F, Doyu M, Sobue G (2006b) Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration. J Neurosci 26:12106–12117PubMedCrossRefGoogle Scholar
  23. Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Tanaka F, Adachi H, Sobue G (2008) Molecular genetics and biomarkers of polyglutamine diseases. Curr Mol Med 8:221–234PubMedCrossRefGoogle Scholar
  24. Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Yabe I, Sasaki H, Aoki M, Morita M, Nakano I, Kanai K, Ito S, Ishikawa K, Mizusawa H, Yamamoto T, Tsuji S, Hasegawa K, Shimohata T, Nishizawa M, Miyajima H, Kanda F, Watanabe Y, Nakashima K, Tsujino A, Yamashita T, Uchino M, Fujimoto Y, Tanaka F, Sobue G (2010) Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) study group. Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multi-center, randomized, double-blind, placebo-controlled trial. Lancet Neurol 9:875–884PubMedCrossRefGoogle Scholar
  25. Kemp MQ, Poort JL, Baqri RM, Lieberman AP, Breedlove SM, Miller KE, Jordan CL (2011) Impaired motoneuronal retrograde transport in two models of SBMA implicates two sites of androgen action. Hum Mol Genet 20:4475–4490PubMedCrossRefGoogle Scholar
  26. Kennedy WR, Alter M, Sung JH (1968) Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 18:671–680PubMedCrossRefGoogle Scholar
  27. Kobayashi Y, Miwa S, Merry DE, Kume A, Mei L, Doyu M, Sobue G (1998) Caspase-3 cleaves the expanded androgen receptor protein of spinal and bulbar muscular atrophy in a polyglutamine repeat length-dependent manner. Biochem Biophys Res Commun 252:145–150PubMedCrossRefGoogle Scholar
  28. La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77–79PubMedCrossRefGoogle Scholar
  29. La Spada AR, Roling DB, Harding AE, Warner CL, Spiegel R, Hausmanowa-Petrusewicz I, Yee WC, Fischbeck KH (1992) Meiotic stability and genotype-phenotype correlation of the trinucleotide repeat in X-linked spinal and bulbar muscular atrophy. Nat Genet 2:301–304PubMedCrossRefGoogle Scholar
  30. Li M, Miwa S, Kobayashi Y, Merry DE, Yamamoto M, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G (1998) Nuclear inclusions of the androgen receptor protein in spinal and bulb muscular atrophy. Ann Neurol 44:249–254PubMedCrossRefGoogle Scholar
  31. Malik B, Nirmalananthan N, Bilsland LG, La Spada AR, Hanna MG, Schiavo G, Gallo JM, Greensmith L (2011) Absence of disturbed axonal transport in spinal and bulbar muscular atrophy. Hum Mol Genet 20:1776–1786PubMedCrossRefGoogle Scholar
  32. McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, Merry D, Chai Y, Paulson H, Sobue G, Fischbeck KH (2002) CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9:2197–2202CrossRefGoogle Scholar
  33. Miller J, Arrasate M, Brooks E, Libeu CP, Legleiter J, Hatters D, Curtis J, Cheung K, Krishnan P, Mitra S, Widjaja K, Shaby BA, Lotz GP, Newhouse Y, Mitchell EJ, Osmand A, Gray M, Thulasiramin V, Saudou F, Segal M, Yang XW, Masliah E, Thompson LM, Muchowski PJ, Weisgraber KH, Finkbeiner S (2011) Identifying polyglutamine protein species in situ that best predict neurodegeneration. Nat Chem Biol 7:925–934PubMedCrossRefGoogle Scholar
  34. Minamiyama M, Katsuno M, Adachi H, Waza M, Sang C, Kobayashi Y, Tanaka F, Doyu M, Inukai A, Sobue G (2004) Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 13:1183–1192PubMedCrossRefGoogle Scholar
  35. Monks DA, Johansen JA, Mo K, Rao P, Eagleson B, Yu Z, Lieberman AP, Breedlove SM, Jordan CL (2007) Overexpression of wild-type androgen receptor in muscle recapitulates polyglutamine disease. Proc Natl Acad Sci USA 104:18259–18264PubMedCrossRefGoogle Scholar
  36. Montie HL, Merry DE (2009) Autophagy and access: understanding the role of androgen receptor subcellular localization in SBMA. Autophagy 5:1194–1197PubMedCrossRefGoogle Scholar
  37. Montie HL, Cho MS, Holder L, Liu Y, Tsvetkov AS, Finkbeiner S, Merry DE (2009) Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 18:1937–1950PubMedCrossRefGoogle Scholar
  38. Morfini G, Pigino G, Szebenyi G, You Y, Pollema S, Brady ST (2006) JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. Nat Neurosci 9:907–916PubMedCrossRefGoogle Scholar
  39. Nagai Y, Inui T, Popiel HA, Fujikake N, Hasegawa K, Urade Y, Goto Y, Naiki H, Toda T (2007) A toxic monomeric conformer of the polyglutamine protein. Nat Struct Mol Biol 14:332–340PubMedCrossRefGoogle Scholar
  40. Nedelsky NB, Pennuto M, Smith RB, Palazzolo I, Moore J, Nie Z, Neale G, Taylor JP (2010) Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy. Neuron 67:936–952PubMedCrossRefGoogle Scholar
  41. Orr CR, Montie HL, Liu Y, Bolzoni E, Jenkins SC, Wilson EM, Joseph JD, McDonnell DP, Merry DE (2010) An interdomain interaction of the androgen receptor is required for its aggregation and toxicity in spinal and bulbar muscular atrophy. J Biol Chem 285:35567–35577PubMedCrossRefGoogle Scholar
  42. Paulsen JS, Hayden M, Stout JC, Langbehn DR, Aylward E, Ross CA, Guttman M, Nance M, Kieburtz K, Oakes D, Shoulson I, Kayson E, Johnson S, Penziner E, Predict-HD Investigators of the Huntington Study Group (2006) Preparing for preventive clinical trials: the Predict-HD study. Arch Neurol 63:883–890PubMedCrossRefGoogle Scholar
  43. Poletti A (2004) The polyglutamine tract of androgen receptor: from functions to dysfunctions in motor neurons. Front Neuroendocrinol 25:1–26PubMedCrossRefGoogle Scholar
  44. Preisler N, Andersen G, Thøgersen F, Crone C, Jeppesen TD, Wibrand F, Vissing J (2009) Effect of aerobic training in patients with spinal and bulbar muscular atrophy (Kennedy disease). Neurology 72:317–323Google Scholar
  45. Ranganathan S, Harmison GG, Meyertholen K, Pennuto M, Burnett BG, Fischbeck KH (2009) Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Hum Mol Genet 18:27–42PubMedCrossRefGoogle Scholar
  46. Sinnreich M, Sorenson EJ, Klein CJ (2004) Neurologic course, endocrine dysfunction and triplet repeat size in spinal bulbar muscular atrophy. Can J Neurol Sci 31:378–382PubMedGoogle Scholar
  47. Sobue G, Hashizume Y, Mukai E, Hirayama M, Mitsuma T, Takahashi A (1989) X-linked recessive bulbospinal neuronopathy - A clinicopathological study. Brain 112:209–232PubMedCrossRefGoogle Scholar
  48. Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL, Thompson LM (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739–743PubMedCrossRefGoogle Scholar
  49. Suzuki K, Katsuno M, Banno H, Takeuchi Y, Atsuta N, Ito M, Watanabe H, Yamashita F, Hori N, Nakamura T, Hirayama M, Tanaka F, Sobue G (2008) CAG repeat size correlates to electrophysiological motor and sensory phenotypes in SBMA. Brain 131:229–239PubMedCrossRefGoogle Scholar
  50. Tabrizi SJ, Langbehn DR, Leavitt BR, Roos RA, Durr A, Craufurd D, Kennard C, Hicks SL, Fox NC, Scahill RI, Borowsky B, Tobin AJ, Rosas HD, Johnson H, Reilmann R, Landwehrmeyer B, Stout JC, TRACK-HD investigators (2009) Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 8:791–801PubMedCrossRefGoogle Scholar
  51. Takahashi T, Kikuchi S, Katada S, Nagai Y, Nishizawa M, Onodera O (2008) Soluble polyglutamine oligomers formed prior to inclusion body formation are cytotoxic. Hum Mol Genet 17:345–356PubMedCrossRefGoogle Scholar
  52. Takeyama K, Ito S, Yamamoto A, Tanimoto H, Furutani T, Kanuka H, Miura M, Tabata T, Kato S (2002) Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 35:855–864PubMedCrossRefGoogle Scholar
  53. Tanaka F, Doyu M, Ito Y, Matsumoto M, Mitsuma T, Abe K, Aoki M, Itoyama Y, Fischbeck KH, Sobue G (1996) Founder effect in spinal and bulbar muscular atrophy (SBMA). Hum Mol Genet 5:1253–1257PubMedCrossRefGoogle Scholar
  54. Taylor JP, Tanaka F, Robitschek J, Sandoval CM, Taye A, Markovic-Plese S, Fischbeck KH (2003) Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum Mol Genet 12:749–757PubMedCrossRefGoogle Scholar
  55. Thomas M, Harrell JM, Morishima Y, Peng HM, Pratt WB, Lieberman AP (2006) Pharmacologic and genetic inhibition of hsp90-dependent trafficking reduces aggregation and promotes degradation of the expanded glutamine androgen receptor without stress protein induction. Hum Mol Genet 15:1876–1883PubMedCrossRefGoogle Scholar
  56. Tokui K, Adachi H, Waza M, Katsuno M, Minamiyama M, Doi H, Tanaka K, Hamazaki J, Murata S, Tanaka F, Sobue G (2009) 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in a SBMA model mouse. Hum Mol Genet 18:898–910PubMedGoogle Scholar
  57. Truant R, Atwal RS, Desmond C, Munsie L, Tran T (2008) Huntington's disease: Revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases. FEBS J 275:4252–4262PubMedCrossRefGoogle Scholar
  58. Waza M, Adachi H, Katsuno M, Minamiyama M, Sang C, Tanaka F, Inukai A, Doyu M, Sobue G (2005) 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat Med 11:1088–1095PubMedCrossRefGoogle Scholar
  59. Williams AJ, Paulson HL (2008) Polyglutamine neurodegeneration: Protein misfolding revisited. Trends Neurosci 31:521–528PubMedCrossRefGoogle Scholar
  60. Yamada M, Sato T, Tsuji S, Takahashi H (2002) Oligodendrocytic polyglutamine pathology in dentatorubral-pallidoluysian atrophy. Ann Neurol 52:670–674PubMedCrossRefGoogle Scholar
  61. Yang Z, Chang YJ, Yu IC, Yeh S, Wu CC, Miyamoto H, Merry DE, Sobue G, Chen LM, Chang SS, Chang C (2007) ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. Nat Med 13:348–353PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
  2. 2.Institute for Advanced ResearchNagoya UniversityNagoyaJapan

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