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X-Linked Spinal and Bulbar Muscular Atrophy: From Clinical Genetic Features and Molecular Pathology to Mechanisms Underlying Disease Toxicity

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Polyglutamine Disorders

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

Abstract

Spinal and Bulbar Muscular Atrophy (SBMA) is an inherited neuromuscular disorder caused by a CAG—polyglutamine (polyQ) repeat expansion in the androgen receptor (AR) gene. Unlike other polyQ diseases, where the function of the native causative protein is unknown, the biology of AR is well understood, and this knowledge has informed our understanding of how native AR function interfaces with polyQ-AR dysfunction. Furthermore, ligand-dependent activation of AR has been linked to SBMA disease pathogenesis, and has led to a thorough study of androgen-mediated effects on polyQ-AR stability, degradation, and post-translational modifications, as well as their roles in the disease process. Transcriptional dysregulation, proteostasis dysfunction, and mitochondrial abnormalities are central to polyQ-AR neurotoxicity, most likely via a ‘change-of-function’ mechanism. Intriguingly, recent work has demonstrated a principal role for skeletal muscle in SBMA disease pathogenesis, indicating that polyQ-AR toxicity initiates in skeletal muscle and results in secondary motor neuron demise. The existence of robust animal models for SBMA has permitted a variety of preclinical trials, driven by recent discoveries of altered cellular processes, and some of this preclinical work has led to human clinical trials. In this chapter, we review SBMA clinical features and disease biology, discuss our current understanding of the cellular and molecular basis of SBMA pathogenesis, and highlight ongoing efforts toward therapy development.

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References

  1. 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(6330):77–79

    Article  Google Scholar 

  2. Bosch-Marce M, Wee CD, Martinez TL, Lipkes CE, Choe DW, Kong L, Van Meerbeke JP, Musaro A, Sumner CJ (2011) Increased IGF-1 in muscle modulates the phenotype of severe SMA mice. Hum Mol Genet 20(9):1844–1853

    Article  CAS  Google Scholar 

  3. Cortes CJ, Ling SC, Guo LT, Hung G, Tsunemi T, Ly L, Tokunaga S, Lopez E, Sopher BL, Bennett CF, Shelton GD, Cleveland DW, La Spada AR (2014) Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy. Neuron 82(2):295–307

    Article  CAS  Google Scholar 

  4. Cortes CJ, Miranda HC, Frankowski H, Batlevi Y, Young JE, Le A, Ivanov N, Sopher BL, Carromeu C, Muotri AR, Garden GA, La Spada AR (2014) Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. Nat Neurosci 17(9):1180–1189

    Article  CAS  Google Scholar 

  5. 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(5):843–854

    Article  CAS  Google Scholar 

  6. Ramzan F, McPhail M, Rao P, Mo K, Halievski K, Swift-Gallant A, Mendoza-Viveros L, Cheng HY, Monks DA (2015) Distinct etiological roles for myocytes and motor neurons in a mouse model of kennedy’s disease/spinobulbar muscular atrophy. J Neurosci 35(16):6444–6451

    Article  CAS  Google Scholar 

  7. Sopher BL, Thomas PS Jr, LaFevre-Bernt MA, Holm IE, Wilke SA, Ware CB, Jin LW, Libby RT, Ellerby LM, La Spada AR (2004) Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 41(5):687–699

    Article  CAS  Google Scholar 

  8. Ono S, Geller LN, Lai EV (1974) TfM mutation and masculinization versus feminization of the mouse central nervous system. Cell 3(3):235–242

    Article  CAS  Google Scholar 

  9. Sato T, Matsumoto T, Yamada T, Watanabe T, Kawano H, Kato S (2003) Late onset of obesity in male androgen receptor-deficient (AR KO) mice. Biochem Biophys Res Commun 300(1):167–171

    Article  CAS  Google Scholar 

  10. Matsumoto T, Sakari M, Okada M, Yokoyama A, Takahashi S, Kouzmenko A, Kato S (2013) The androgen receptor in health and disease. Annu Rev Physiol 75:201–224

    Article  CAS  Google Scholar 

  11. Clark PE, Irvine RA, Coetzee GA (2003) The androgen receptor CAG repeat and prostate cancer risk. Methods Mol Med 81:255–266

    CAS  PubMed  Google Scholar 

  12. Soraru G, D’Ascenzo C, Polo A, Palmieri A, Baggio L, Vergani L, Gellera C, Moretto G, Pegoraro E, Angelini C (2008) Spinal and bulbar muscular atrophy: skeletal muscle pathology in male patients and heterozygous females. J Neurol Sci 264(1–2):100–105

    Article  CAS  Google Scholar 

  13. Katsuno M, Tanaka F, Adachi H, Banno H, Suzuki K, Watanabe H, Sobue G (2012) Pathogenesis and therapy of spinal and bulbar muscular atrophy (SBMA). Prog Neurobiol 99:246–256

    Article  CAS  Google Scholar 

  14. 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(1):145–150

    Article  CAS  Google Scholar 

  15. Jochum T, Ritz ME, Schuster C, Funderburk SF, Jehle K, Schmitz K, Brinkmann F, Hirtz M, Moss D, Cato AC (2012) Toxic and non-toxic aggregates from the SBMA and normal forms of androgen receptor have distinct oligomeric structures. Biochimica et biophysica acta 1822(6):1070–1078

    Article  CAS  Google Scholar 

  16. 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 J Neurol 128(Pt 3):659–670

    Article  Google Scholar 

  17. Li M, Chevalier-Larsen ES, Merry DE, Diamond MI (2007) Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy. J Biol Chem 282(5):3157–3164

    Article  CAS  Google Scholar 

  18. 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 bulbar muscular atrophy. Ann Neurol 44(2):249–254

    Article  CAS  Google Scholar 

  19. La Spada AR, Taylor JP (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11(4):247–258

    Article  Google Scholar 

  20. Doi H, Adachi H, Katsuno M, Minamiyama M, Matsumoto S, Kondo N, Miyazaki Y, Iida M, Tohnai G, Qiang Q, Tanaka F, Yanagawa T, Warabi E, Ishii T, Sobue G (2013) p62/SQSTM1 differentially removes the toxic mutant androgen receptor via autophagy and inclusion formation in a spinal and bulbar muscular atrophy mouse model. J Neurosci 33(18):7710–7727

    Article  CAS  Google Scholar 

  21. 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(6):768–773

    Article  CAS  Google Scholar 

  22. 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 U S A 104(46):18259–18264

    Article  CAS  Google Scholar 

  23. 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(6):936–952

    Article  CAS  Google Scholar 

  24. 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(5):855–864

    Article  CAS  Google Scholar 

  25. Pennuto M, Basso M (2015) In vitro and in vivo modeling of spinal and bulbar muscular atrophy. J Mol Neurosci 58:365–373

    Article  Google Scholar 

  26. Chevalier-Larsen ES, O’Brien CJ, Wang H, 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(20):4778–4786

    Article  CAS  Google Scholar 

  27. Pandey UB, Nie Z, Batlevi Y, McCray BA, Ritson GP, Nedelsky NB, Schwartz SL, DiProspero NA, Knight MA, Schuldiner O, Padmanabhan R, Hild M, Berry DL, Garza D, Hubbert CC, Yao TP, Baehrecke EH, Taylor JP (2007) HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS. Nature 447(7146):859–863

    Article  CAS  Google Scholar 

  28. Ellerby LM, Hackam AS, Propp SS, Ellerby HM, Rabizadeh S, Cashman NR, Trifiro MA, Pinsky L, Wellington CL, Salvesen GS, Hayden MR, Bredesen DE (1999) Kennedy’s disease: caspase cleavage of the androgen receptor is a crucial event in cytotoxicity. J Neurochem 72(1):185–195

    Article  CAS  Google Scholar 

  29. Young JE, Garden GA, Martinez RA, Tanaka F, Sandoval CM, Smith AC, Sopher BL, Lin A, Fischbeck KH, Ellerby LM, Morrison RS, Taylor JP, La Spada AR (2009) Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk. J Neurosci Off J Soc Neurosci 29(7):1987–1997

    Article  CAS  Google Scholar 

  30. Anbalagan M, Huderson B, Murphy L, Rowan BG (2012) Post-translational modifications of nuclear receptors and human disease. Nucl Recept Signal 10:e001

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Palazzolo I, Stack C, Kong L, Musaro A, Adachi H, Katsuno M, Sobue G, Taylor JP, Sumner CJ, Fischbeck KH, Pennuto M (2009) Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. Neuron 63(3):316–328

    Article  CAS  Google Scholar 

  32. Zboray L, Pluciennik A, Curtis D, Liu Y, Berman-Booty LD, Orr C, Kesler CT, Berger T, Gioeli D, Paschal BM, Merry DE (2015) Preventing the Androgen Receptor N/C Interaction Delays Disease Onset in a Mouse Model of SBMA. Cell reports 13(10):2312–2323

    Article  CAS  Google Scholar 

  33. LaFevre-Bernt MA, Ellerby LM (2003) Kennedy’s disease. Phosphorylation of the polyglutamine-expanded form of androgen receptor regulates its cleavage by caspase-3 and enhances cell death. J Biol Chem 278(37):34918–34924

    Article  CAS  Google Scholar 

  34. Todd TW, Kokubu H, Miranda HC, Cortes CJ, La Spada AR, Lim J (2015) Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy. eLife 4:e08493

    Google Scholar 

  35. Ju H, Kokubu H, Todd TW, Kahle JJ, Kim S, Richman R, Chirala K, Orr HT, Zoghbi HY, Lim J (2013) Polyglutamine disease toxicity is regulated by Nemo-like kinase in spinocerebellar ataxia type 1. J Neurosci Off J Soc Neurosci 33(22):9328–9336

    Article  CAS  Google Scholar 

  36. Kaikkonen S, Jaaskelainen T, Karvonen U, Rytinki MM, Makkonen H, Gioeli D, Paschal BM, Palvimo JJ (2009) SUMO-specific protease 1 (SENP1) reverses the hormone-augmented SUMOylation of androgen receptor and modulates gene responses in prostate cancer cells. Mol Endocrinol 23(3):292–307

    Article  CAS  Google Scholar 

  37. Mukherjee S, Cruz-Rodriguez O, Bolton E, Iniguez-Lluhi JA (2012) The in vivo role of androgen receptor SUMOylation as revealed by androgen insensitivity syndrome and prostate cancer mutations targeting the proline/glycine residues of synergy control motifs. J Biol Chem 287(37):31195–31206

    Article  CAS  Google Scholar 

  38. Mukherjee S, Thomas M, Dadgar N, Lieberman AP, Iniguez-Lluhi JA (2009) Small ubiquitin-like modifier (SUMO) modification of the androgen receptor attenuates polyglutamine-mediated aggregation. J Biol Chem 284(32):21296–21306

    Article  CAS  Google Scholar 

  39. Chan HY, Warrick JM, Andriola I, Merry D, Bonini NM (2002) Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet 11(23):2895–2904

    Article  CAS  Google Scholar 

  40. Chua JP, Reddy SL, Yu Z, Giorgetti E, Montie HL, Mukherjee S, Higgins J, McEachin RC, Robins DM, Merry DE, Iniguez-Lluhi JA, Lieberman AP (2015) Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease. J Clin Investig 125(2):831–845

    Article  Google Scholar 

  41. Scaramuzzino C, Casci I, Parodi S, Lievens PM, Polanco MJ, Milioto C, Chivet M, Monaghan J, Mishra A, Badders N, Aggarwal T, Grunseich C, Sambataro F, Basso M, Fackelmayer FO, Taylor JP, Pandey UB, Pennuto M (2015) Protein arginine methyltransferase 6 enhances polyglutamine-expanded androgen receptor function and toxicity in spinal and bulbar muscular atrophy. Neuron 85(1):88–100

    Article  CAS  Google Scholar 

  42. Lieberman AP, Harmison G, Strand AD, Olson JM, Fischbeck KH (2002) Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor. Hum Mol Genet 11(17):1967–1976

    Article  CAS  Google Scholar 

  43. Montie HL, Pestell RG, Merry DE (2011) SIRT1 modulates aggregation and toxicity through deacetylation of the androgen receptor in cell models of SBMA. J Neurosci 31(48):17425–17436

    Article  CAS  Google Scholar 

  44. Mhatre AN, Trifiro MA, Kaufman M, Kazemi-Esfarjani P, Figlewicz D, Rouleau G, Pinsky L (1993) Reduced transcriptional regulatory competence of the androgen receptor in X-linked spinal and bulbar muscular atrophy. Nat Genet 5(2):184–188

    Article  CAS  Google Scholar 

  45. Mo K, Razak Z, Rao P, Yu Z, Adachi H, Katsuno M, Sobue G, Lieberman AP, Westwood JT, Monks DA (2010) Microarray analysis of gene expression by skeletal muscle of three mouse models of Kennedy disease/spinal bulbar muscular atrophy. PLoS ONE 5(9):e12922

    Article  Google Scholar 

  46. 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(46):35567–35577

    Article  CAS  Google Scholar 

  47. 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(11):1937–1950

    Article  CAS  Google Scholar 

  48. Thomas PS Jr, Fraley GS, Damian V, Woodke LB, Zapata F, Sopher BL, Plymate SR, La Spada AR (2006) Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy. Hum Mol Genet 15(14):2225–2238

    Article  CAS  Google Scholar 

  49. McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, Merry D, Chai Y, Paulson H, Sobue G, Fischbeck KH (2000) CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9(14):2197–2202

    Article  CAS  Google Scholar 

  50. 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(11):1183–1192

    Article  CAS  Google Scholar 

  51. Nucifora FC Jr, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, Takahashi H, Tsuji S, Troncoso J, Dawson VL, Dawson TM, Ross CA (2001) Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 291(5512):2423–2428

    Article  CAS  Google Scholar 

  52. 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) Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 9(9):875–884

    Article  CAS  Google Scholar 

  53. 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(1):27–42

    Article  CAS  Google Scholar 

  54. Katsuno M, Adachi H, Minamiyama M, Waza M, Tokui K, Banno H, Suzuki K, Onoda Y, Tanaka F, Doyu M, Sobue G (2006) Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 26(47):12106–12117

    Article  CAS  Google Scholar 

  55. Cowan KJ, Diamond MI, Welch WJ (2003) Polyglutamine protein aggregation and toxicity are linked to the cellular stress response. Hum Mol Genet 12(12):1377–1391

    Article  CAS  Google Scholar 

  56. 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 U S A 102(46):16801–16806

    Article  CAS  Google Scholar 

  57. Kondo N, Katsuno M, Adachi H, Minamiyama M, Doi H, Matsumoto S, Miyazaki Y, Iida M, Tohnai G, Nakatsuji H, Ishigaki S, Fujioka Y, Watanabe H, Tanaka F, Nakai A, Sobue G (2013) Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration. Nat Commun 4:1405

    Article  Google Scholar 

  58. 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(6):2203–2211

    CAS  PubMed  Google Scholar 

  59. Bailey CK, Andriola IF, Kampinga HH, Merry DE (2002) Molecular chaperones enhance the degradation of expanded polyglutamine repeat androgen receptor in a cellular model of spinal and bulbar muscular atrophy. Hum Mol Genet 11(5):515–523

    Article  CAS  Google Scholar 

  60. Howarth JL, Kelly S, Keasey MP, Glover CP, Lee YB, Mitrophanous K, Chapple JP, Gallo JM, Cheetham ME, Uney JB (2007) Hsp40 molecules that target to the ubiquitin-proteasome system decrease inclusion formation in models of polyglutamine disease. Mol Ther J Am Soc Gene Ther 15(6):1100–1105

    Article  CAS  Google Scholar 

  61. Ishihara K, Yamagishi N, Saito Y, Adachi H, Kobayashi Y, Sobue G, Ohtsuka K, Hatayama T (2003) Hsp105alpha suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity. J Biol Chem 278(27):25143–25150

    Article  CAS  Google Scholar 

  62. Rusmini P, Crippa V, Giorgetti E, Boncoraglio A, Cristofani R, Carra S, Poletti A (2013) Clearance of the mutant androgen receptor in motoneuronal models of spinal and bulbar muscular atrophy. Neurobiol Aging 34(11):2585–2603

    Article  CAS  Google Scholar 

  63. Rusmini P, Polanco MJ, Cristofani R, Cicardi ME, Meroni M, Galbiati M, Piccolella M, Messi E, Giorgetti E, Lieberman AP, Milioto C, Rocchi A, Aggarwal T, Pennuto M, Crippa V, Poletti A (2015) Aberrant autophagic response in the muscle of a knock-in mouse model of spinal and bulbar muscular atrophy. Sci Rep 5:15174

    Article  CAS  Google Scholar 

  64. Cortes CJ, La Spada AR (2015) Autophagy in polyglutamine disease: Imposing order on disorder or contributing to the chaos? Mol Cell Neurosci 66(Pt A):53–61

    Article  CAS  Google Scholar 

  65. Rusmini P, Bolzoni E, Crippa V, Onesto E, Sau D, Galbiati M, Piccolella M, Poletti A (2010) Proteasomal and autophagic degradative activities in spinal and bulbar muscular atrophy. Neurobiol Dis 40(2):361–369

    Article  CAS  Google Scholar 

  66. 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(7):749–757

    Article  CAS  Google Scholar 

  67. Tohnai G, Adachi H, Katsuno M, Doi H, Matsumoto S, Kondo N, Miyazaki Y, Iida M, Nakatsuji H, Qiang Q, Ding Y, Watanabe H, Yamamoto M, Ohtsuka K, Sobue G (2014) Paeoniflorin eliminates a mutant AR via NF-YA-dependent proteolysis in spinal and bulbar muscular atrophy. Hum Mol Genet 23(13):3552–3565

    Article  CAS  Google Scholar 

  68. 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(10):1088–1095

    Article  CAS  Google Scholar 

  69. Rusmini P, Simonini F, Crippa V, Bolzoni E, Onesto E, Cagnin M, Sau D, Ferri N, Poletti A (2011) 17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy. Neurobiol Dis 41(1):83–95

    Article  CAS  Google Scholar 

  70. Lieberman AP, Yu Z, Murray S, Peralta R, Low A, Guo S, Yu XX, Cortes CJ, Bennett CF, Monia BP, La Spada AR, Hung G (2014) Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy. Cell reports 7(3):774–784

    Article  CAS  Google Scholar 

  71. Chua JP, Reddy SL, Merry DE, Adachi H, Katsuno M, Sobue G, Robins DM, Lieberman AP (2014) Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy. Hum Mol Genet 23(5):1376–1386

    Article  CAS  Google Scholar 

  72. Sandri M, Coletto L, Grumati P, Bonaldo P (2013) Misregulation of autophagy and protein degradation systems in myopathies and muscular dystrophies. J Cell Sci 126(Pt 23):5325–5333

    Article  CAS  Google Scholar 

  73. Yu Z, Wang AM, Adachi H, Katsuno M, Sobue G, Yue Z, Robins DM, Lieberman AP (2011) Macroautophagy is regulated by the UPR-mediator CHOP and accentuates the phenotype of SBMA mice. PLoS Genet 7(10):e1002321

    Article  CAS  Google Scholar 

  74. Piccioni F, Pinton P, Simeoni S, Pozzi P, Fascio U, Vismara G, Martini L, Rizzuto R, Poletti A (2002) Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motor neuronal processes. FASEB J Off Publ Fed Am Soc Exp Biol 16(11):1418–1420

    CAS  Google Scholar 

  75. Thomas M, Yu Z, Dadgar N, Varambally S, Yu J, Chinnaiyan AM, Lieberman AP (2005) The unfolded protein response modulates toxicity of the expanded glutamine androgen receptor. J Biol Chem 280(22):21264–21271

    Article  CAS  Google Scholar 

  76. Montague K, Malik B, Gray AL, La Spada AR, Hanna MG, Szabadkai G, Greensmith L (2014) Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy. Brain 137(Pt 7):1894–1906

    Article  Google Scholar 

  77. 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(7):907–916

    Article  CAS  Google Scholar 

  78. 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(22):4475–4490

    Article  CAS  Google Scholar 

  79. 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(9):1776–1786

    Article  CAS  Google Scholar 

  80. Yu Z, Dadgar N, Albertelli M, Gruis K, Jordan C, Robins DM, Lieberman AP (2006) Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model. J Clin Invest 116(10):2663–2672

    Article  CAS  Google Scholar 

  81. Rocchi A, Milioto C, Parodi S, Armirotti A, Borgia D, Pellegrini M, Urciuolo A, Molon S, Morbidoni V, Marabita M, Romanello V, Gatto P, Blaauw B, Bonaldo P, Sambataro F, Robins DM, Lieberman AP, Soraru G, Vergani L, Sandri M, Pennuto M (2016) Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet. Acta Neuropathol 132:127–144

    Article  CAS  Google Scholar 

  82. Katsuno M, Adachi H, Minamiyama M, Waza M, Doi H, Kondo N, Mizoguchi H, Nitta A, Yamada K, Banno H, Suzuki K, Tanaka F, Sobue G (2010) Disrupted transforming growth factor-beta signaling in spinal and bulbar muscular atrophy. J Neurosci 30(16):5702–5712

    Article  CAS  Google Scholar 

  83. Sahashi K, Katsuno M, Hung G, Adachi H, Kondo N, Nakatsuji H, Tohnai G, Iida M, Bennett CF, Sobue G (2015) Silencing neuronal mutant androgen receptor in a mouse model of spinal and bulbar muscular atrophy. Hum Mol Genet 24(21):5985–5994

    Article  CAS  Google Scholar 

  84. Keiser MS, Boudreau RL, Davidson BL (2014) Broad therapeutic benefit after RNAi expression vector delivery to deep cerebellar nuclei: implications for spinocerebellar ataxia type 1 therapy. Mol Ther J Am Soc Gene Ther 22(3):588–595

    Article  CAS  Google Scholar 

  85. Rodriguez-Lebron E, Costa Mdo C, 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 J Am Soc Gene Ther 21(10):1909–1918

    Article  CAS  Google Scholar 

  86. Miyazaki Y, Adachi H, Katsuno M, Minamiyama M, Jiang YM, Huang Z, Doi H, Matsumoto S, Kondo N, Iida M, Tohnai G, Tanaka F, Muramatsu S, Sobue G (2012) Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2. Nat Med 18(7):1136–1141

    Article  CAS  Google Scholar 

  87. Pourshafie N, Lee PR, Chen KL, Harmison GG, Bott LC, Katsuno M, Sobue G, Burnett BG, Fischbeck KH, Rinaldi C (2016) MiR-298 counteracts mutant androgen receptor toxicity in spinal and bulbar muscular atrophy. Mol Ther J Am Soc Gene Ther 24:937–945

    Article  CAS  Google Scholar 

  88. 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 an SBMA model mouse. Hum Mol Genet 18(5):898–910

    Article  CAS  Google Scholar 

  89. Malik B, Nirmalananthan N, Gray AL, La Spada AR, Hanna MG, Greensmith L (2013) Co-induction of the heat shock response ameliorates disease progression in a mouse model of human spinal and bulbar muscular atrophy: implications for therapy. Brain J Neurol 136(Pt 3):926–943

    Article  Google Scholar 

  90. Giorgetti E, Rusmini P, Crippa V, Cristofani R, Boncoraglio A, Cicardi ME, Galbiati M, Poletti A (2015) Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy. Hum Mol Genet 24(1):64–75

    Article  CAS  Google Scholar 

  91. Castillo K, Nassif M, Valenzuela V, Rojas F, Matus S, Mercado G, Court FA, van Zundert B, Hetz C (2013) Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy 9(9):1308–1320

    Article  CAS  Google Scholar 

  92. 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(3):520–526

    Article  CAS  Google Scholar 

  93. 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(2):140–150

    Article  CAS  Google Scholar 

  94. Fernandez-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 randomised placebo-controlled trial. Lancet Neurol 10(2):140–147

    Article  CAS  Google Scholar 

  95. 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(3):348–353

    Article  CAS  Google Scholar 

  96. Bott LC, Badders NM, Chen KL, Harmison GG, Bautista E, Shih CC, Katsuno M, Sobue G, Taylor JP, Dantuma NP, Fischbeck KH, Rinaldi C (2016) A small-molecule Nrf1 and Nrf2 activator mitigates polyglutamine toxicity in spinal and bulbar muscular atrophy. Hum Mol Genet 25:1979–1989

    Article  CAS  Google Scholar 

  97. Rinaldi C, Bott LC, Chen KL, Harmison GG, Katsuno M, Sobue G, Pennuto M, Fischbeck KH (2012) Insulinlike growth factor (IGF)-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy. Mol Med 18:1261–1268

    Article  CAS  Google Scholar 

  98. Ding Y, Adachi H, Katsuno M, Huang Z, Jiang YM, Kondo N, Iida M, Tohnai G, Nakatsuji H, Funakoshi H, Nakamura T, Sobue G (2015) Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration. Biochem Biophys Res Commun 468(4):677–683

    Article  CAS  Google Scholar 

  99. Querin G, D’Ascenzo C, Peterle E, Ermani M, Bello L, Melacini P, Morandi L, Mazzini L, Silani V, Raimondi M, Mandrioli J, Romito S, Angelini C, Pegoraro E, Soraru G (2013) Pilot trial of clenbuterol in spinal and bulbar muscular atrophy. Neurology 80(23):2095–2098

    Article  CAS  Google Scholar 

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Acknowledgements

Our research on SBMA is supported by funding from the Kennedy’s Disease Association, the Muscular Dystrophy Association, and the N.I.H. (R01 NS100023).

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  1. Departments of Cellular & Molecular Medicine, Department of Neurosciences and Pediatrics, Division of Biological Sciences, Institute for Genomic Medicine and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92037, USA

    Constanza J. Cortes & Albert R. La Spada

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  1. Constanza J. Cortes
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  2. Albert R. La Spada
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Correspondence to Albert R. La Spada .

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  1. Department of Biomedical Sciences and Medicine; Centre for Biomedical Research and Algarve Biomedical Center, University of Algarve, Faro, Portugal

    Clévio Nóbrega

  2. Center for Neuroscience and Cell Biology and Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

    Luís Pereira de Almeida

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Cortes, C.J., La Spada, A.R. (2018). X-Linked Spinal and Bulbar Muscular Atrophy: From Clinical Genetic Features and Molecular Pathology to Mechanisms Underlying Disease Toxicity. In: Nóbrega, C., Pereira de Almeida, L. (eds) Polyglutamine Disorders. Advances in Experimental Medicine and Biology, vol 1049. Springer, Cham. https://doi.org/10.1007/978-3-319-71779-1_5

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