Skip to main content
SpringerLink
Log in

Clinical Features and Molecular Mechanisms of Spinal and Bulbar Muscular Atrophy (SBMA)

  • Chapter
Diseases of DNA Repair

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 685))

Abstract

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of this disease is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. SBMA exclusively occurs in adult males, whereas both heterozygous and homozygous females are usually asymptomatic. Lower motor neurons in the anterior horn of the spinal cord and those in the brainstem motor nuclei are predominantly affected in SBMA, and other neuronal and nonneuronal tissues are also widely involved to some extent. Testosterone-dependent nuclear accumulation of the pathogenic AR protein has been considered to be a fundamental step of neurodegenerative process, which is followed by several molecular events such as transcriptional dysregulation, axonal transport disruption and mitochondrial dysfunction. Results of animal studies suggest that androgen deprivation and activation of protein quality control systems are potential therapies fo

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Fischbeck KH. Kennedy disease. J Inherit Metab Dis 1997; 20:152–158.

    Article  CAS  PubMed  Google Scholar 

  2. Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 1968; 18:671–680.

    CAS  PubMed  Google Scholar 

  3. Katsuno M, Adachi H, Waza M et al. Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA). Exp Neurol 2006; 200:8–18.

    CAS  PubMed  Google Scholar 

  4. Pachatz C, Terracciano C, Desiato MT et al. Upper motor neuron involvement in X-linked recessive bulbospinal muscular atrophy. Clin Neurophysiol 2007; 118:262–268.

    Article  CAS  PubMed  Google Scholar 

  5. Atsuta N, Watanabe H, Ito M et al. Natural history of spinal and bulbar muscular atrophy (SBMA): a study of 223 Japanese patients. Brain 2006; 129:1446–1455.

    Article  PubMed  Google Scholar 

  6. Takeuchi Y, Katsuno M, Banno H et al. Walking capacity evaluated by the 6-minute walk test in spinal and bulbar muscular atrophy. Muscle Nerve 2008; 38:964–971.

    Article  PubMed  Google Scholar 

  7. Sperfeld AD, Hanemann CO, Ludolph AC et al. Laryngospasm: an underdiagnosed symptom of X-linked spinobulbar muscular atrophy. Neurology 2005; 64:753–754.

    PubMed  Google Scholar 

  8. Suzuki K, Katsuno M, Banno H et al. CAG repeat size correlates to electrophysiological motor and sensory phenotypes in SBMA. Brain 2008; 131:229–239.

    Article  PubMed  Google Scholar 

  9. Inoue K, Hemmi S, Miyaishi M et al. Muscular fatigue and decremental response to repetitive nerve stimulation in X-linked spinobulbar muscular atrophy. Eur J Neurol 2009; 16:76–80.

    Article  CAS  PubMed  Google Scholar 

  10. Dejager S, Bry-Gauillard H, Bruckert E et al. A comprehensive endocrine description of Kennedy’s disease revealing androgen insensitivity linked to CAG repeat length. J Clin Endocr Metab 2002; 87:3893–3901.

    Article  CAS  PubMed  Google Scholar 

  11. Sobue G, Doyu M, Kachi T et al. Subclinical phenotypic expressions in heterozygous females of X-linked recessive bulbospinal neuronopathy. J Neurol Sci 1993; 117:74–78.

    Article  CAS  PubMed  Google Scholar 

  12. La Spada AR, Wilson EM, Lubahn DB et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991; 352:77–79.

    Article  PubMed  Google Scholar 

  13. Andrew SE, Goldberg YP, Hayden MR. Rethinking genotype and phenotype correlations in polyglutamine expansion disorders. Hum Mol Genet 1997; 6:2005–2010.

    Article  CAS  PubMed  Google Scholar 

  14. Gatchel JR, Zoghbi HY. Diseases of unstable repeat expansion: mechanism and principles. Nat Rev Genet 2005; 6:743–755.

    Article  CAS  PubMed  Google Scholar 

  15. Tanaka F, Doyu M, Ito Y et al. Founder effect in spinal and bulbar muscular atrophy (SBMA). Hum Mol Genet 1996; 5:1253–1257.

    Article  CAS  PubMed  Google Scholar 

  16. Doyu M, Sobue G, Mukai E et al. Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG repeat in androgen receptor gene. Ann Neurol 1992; 32:707–710.

    Article  CAS  PubMed  Google Scholar 

  17. Palazzolo I, Gliozzi A, Rusmini P et al. The role of the polyglutamine tract in androgen receptor. J Steroid Biochem Mol Biol 2008; 108:245–253.

    Article  CAS  PubMed  Google Scholar 

  18. Sobue G, Hashizume Y, Mukai E et al. X-linked recessive bulbospinal neuronopathy. A clinicopathological study. Brain 1989; 112:209–232.

    Article  PubMed  Google Scholar 

  19. Li M, Miwa S, Kobayashi Y et al. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann Neurol 1998; 44:249–254.

    Article  CAS  PubMed  Google Scholar 

  20. Arrasate M, Mitra S, Schweitzer ES et al. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 2004; 431:805–810.

    Article  CAS  PubMed  Google Scholar 

  21. Nagai Y, Inui T, Popiel HA et al. A toxic monomeric conformer of the polyglutamine protein. Nat Struct Mol Biol 2007; 14:332–340.

    Article  CAS  PubMed  Google Scholar 

  22. Adachi H, Katsuno M, Minamiyama M et al. Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients. Brain 2005; 128:659–670.

    Article  PubMed  Google Scholar 

  23. Banno H, Adachi H, Katsuno M et al. Mutant androgen receptor accumulation in SBMA scrotal skin: a pathogenic marker. Ann Neurol 2006; 59:520–526.

    Article  CAS  PubMed  Google Scholar 

  24. Poletti A. The polyglutamine tract of androgen receptor: from functions to dysfunctions in motor neurons. Front. Neuroendocrinol 2004; 25:1–26.

    Article  CAS  Google Scholar 

  25. Adachi H, Kume A, Li M 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 2001; 10:1039–1048.

    Article  CAS  PubMed  Google Scholar 

  26. Wyttenbach A. Role of heat shock proteins during polyglutamine neurodegeneration: mechanisms and hypothesis. J Mol Neurosci 2004; 23:69–96.

    Article  CAS  PubMed  Google Scholar 

  27. Muchowski PJ, Wacker JL. Modulation of neurodegeneration by molecular chaperones. Nat Rev Neurosci 2005; 6:11–22.

    Article  CAS  PubMed  Google Scholar 

  28. Li M, Chevalier-Larsen ES, Merry DE et al. Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy. J Biol Chem 2007; 282:3157–3164.

    Article  CAS  PubMed  Google Scholar 

  29. Katsuno M, Adachi H, Kume A et al. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 2002; 35:843–854.

    Article  CAS  PubMed  Google Scholar 

  30. Yu Z, Dadgar N, Albertelli M et al. Abnormalities of germ cell maturation and sertoli cell cytoskeleton in androgen receptor 113 CAG knock-in mice reveal toxic effects of the mutant protein. Am J Pathol 2006; 168:195–204.

    Article  CAS  PubMed  Google Scholar 

  31. Montie HL, Cho MS, Holder L et al. Cytoplasmic Retention of Polyglutamine-Expanded Androgen Receptor Ameliorates Disease via Autophagy in a Mouse Model of Spinal and Bulbar Muscular Atrophy. Hum Mol Genet 2009 (Epub ahead of print).

    Google Scholar 

  32. Takeyama K, Ito S, Yamamoto A et al. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 2002; 35:855–864.

    Article  CAS  PubMed  Google Scholar 

  33. Chevalier-Larsen ES, O’Brien CJ, Wang H 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 2004; 24:4778–4786.

    Article  CAS  PubMed  Google Scholar 

  34. Katsuno M, Adachi H, Minamiyama M et al. Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration. J Neurosci 2006; 26:12106–12117.

    Article  CAS  PubMed  Google Scholar 

  35. Schmidt BJ, Greenberg CR, Allingham-Hawkins DJ et al. Expression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women. Neurology 2002; 59:770–772.

    PubMed  Google Scholar 

  36. Kinirons P, Rouleau GA. Administration of testosterone results in reversible deterioration in Kennedy’s disease. J Neurol Neurosurg Psychiatry 2008; 79:106–107.

    Article  CAS  PubMed  Google Scholar 

  37. Lin X, Antalffy B, Kang D et al. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci 2000; 3:157–163.

    Article  CAS  PubMed  Google Scholar 

  38. Luthi-Carter R, Strand A, Peters NL et al. Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 2000; 9:1259–1271.

    Article  CAS  PubMed  Google Scholar 

  39. Hay DG, Sathasivam K, Tobaben S et al. Progressive decrease in chaperone protein levels in a mouse model of Huntington’s disease and induction of stress proteins as a therapeutic approach. Hum Mol Genet 2004; 13:1389–1405.

    Article  CAS  PubMed  Google Scholar 

  40. Katsuno M, Sang C, Adachi H et al. Pharmacological induction of heat-shock proteins alleviates polyglutamine-mediated motor neuron disease. Proc Natl Acad Sci USA 2005; 102:16801–16806.

    Article  CAS  PubMed  Google Scholar 

  41. Nucifora FC Jr, Sasaki M, Peters MF et al. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 2001; 291:2423–2428.

    Article  CAS  PubMed  Google Scholar 

  42. Steffan JS, Bodai L, Pallos J et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001; 413:739–743.

    Article  CAS  PubMed  Google Scholar 

  43. Minamiyama M, Katsuno M, Adachi H et al. Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 2004; 13:1183–1192.

    Article  CAS  PubMed  Google Scholar 

  44. Sopher BL, Thomas PS Jr, LaFevre-Bernt MA et al. Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 2004; 41:687–699.

    Article  CAS  PubMed  Google Scholar 

  45. Suzuki E, Zhao Y, Ito S et al. Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity. Proc Natl Acad Sci USA 2009; 106:3818–3822.

    Article  CAS  PubMed  Google Scholar 

  46. Puls I, Jonnakuty C, LaMonte BH et al. Mutant dynactin in motor neuron disease. Nat Genet 2003; 33:455–456.

    Article  CAS  PubMed  Google Scholar 

  47. Hafezparast M, Klocke R, Ruhrberg C et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 2003; 300:808–812.

    Article  CAS  PubMed  Google Scholar 

  48. Morfini G, Pigino G, Szebenyi G et al. JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport. Nat Neurosci 2006; 9:907–916.

    Article  CAS  PubMed  Google Scholar 

  49. Young JE, Garden GA, Martinez RA et al. Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk. J Neurosci 2009; 29:1987–1997.

    Article  CAS  PubMed  Google Scholar 

  50. Ranganathan S, Harmison GG, Meyertholen K et al. Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Hum Mol Genet 2009; 18:27–42.

    Article  CAS  PubMed  Google Scholar 

  51. Custer SK, Garden GA, Gill N et al. Bergmann glia expression of polyglutamine-expanded ataxin-7 produces neurodegeneration by impairing glutamate transport. Nat Neurosci 2006; 9:1302–1311.

    Article  CAS  PubMed  Google Scholar 

  52. Monks DA, Johansen JA, Mo K et al. Overexpression of wild-type androgen receptor in muscle recapitulates polyglutamine disease. Proc Natl Acad Sci USA 2007; 104:18259–18264.

    Article  CAS  PubMed  Google Scholar 

  53. Katsuno M, Adachi H, Doyu M et al. Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy. Nat Med 2003; 9:768–773.

    Article  CAS  PubMed  Google Scholar 

  54. Banno H, Katsuno M, Suzuki K et al. Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. Ann Neurol 2009; 65:140–150.

    Article  CAS  PubMed  Google Scholar 

  55. Yang Z, Chang YJ, Yu IC et al. ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor. Nat Med 2007; 13:348–353.

    Article  CAS  PubMed  Google Scholar 

  56. Palazzolo I, Burnett BG, Young JE et al. Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity. Hum Mol Genet 2007; 16:1593–1603.

    Article  CAS  PubMed  Google Scholar 

  57. Tokui K, Adachi H, Waza M et al. 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse. Hum Mol Genet 2009; 18:898–910.

    CAS  PubMed  Google Scholar 

  58. Waza M, Adachi H, Katsuno M et al. 17-AAG, an Hsp90 inhibitor, ameliorates polyglutamine-mediated motor neuron degeneration. Nat Med 2005; 11:1088–1095.

    Article  CAS  PubMed  Google Scholar 

  59. Adachi H, Katsuno M, Minamiyama M 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 2003; 23:2203–2211.

    CAS  PubMed  Google Scholar 

  60. Bailey CK, Andriola IF, Kampinga HH et al. Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy. Hum Mol Genet 2002; 11:515–523.

    Article  CAS  PubMed  Google Scholar 

  61. Adachi H, Waza M, Tokui K et al. CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model. J Neurosci 2007; 27:5115–5126.

    Article  CAS  PubMed  Google Scholar 

  62. Ying M, Xu R, Wu X et al. Sodium butyrate ameliorates histone hypoacetylation and neurodegenerative phenotypes in a mouse model for DRPLA. J Biol Chem 2006; 281:12580–12586.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Masahisa Katsuno, Haruhiko Banno, Keisuke Suzuki, Hiroaki Adachi, Fumiaki Tanaka & Gen Sobue

  2. Institute for Advanced Research, Nagoya University, Nagoya, Japan

    Masahisa Katsuno

Authors
  1. Masahisa Katsuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haruhiko Banno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keisuke Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroaki Adachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fumiaki Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gen Sobue
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Masahisa Katsuno or Gen Sobue .

Editor information

Editors and Affiliations

  1. School of Science and Technology, Nottingham Trent University, Nottingham, UK

    Shamim I. Ahmad BSc, MSc, PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Katsuno, M., Banno, H., Suzuki, K., Adachi, H., Tanaka, F., Sobue, G. (2010). Clinical Features and Molecular Mechanisms of Spinal and Bulbar Muscular Atrophy (SBMA). In: Ahmad, S.I. (eds) Diseases of DNA Repair. Advances in Experimental Medicine and Biology, vol 685. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6448-9_6

Download citation

Publish with us

Policies and ethics

Search

Navigation