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Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy

Nature Medicine volume 9, pages 768–773 (2003)Cite this article

Abstract

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease that affects males. It is caused by the expansion of a polyglutamine (polyQ) tract in androgen receptors. Female carriers are usually asymptomatic. No specific treatment has been established. Our transgenic mouse model carrying a full-length human androgen receptor with expanded polyQ has considerable gender-related motor impairment. This phenotype was abrogated by castration, which prevented nuclear translocation of mutant androgen receptors. We examined the effect of androgen-blockade drugs on our mouse model. Leuprorelin, a lutenizing hormone–releasing hormone (LHRH) agonist that reduces testosterone release from the testis, rescued motor dysfunction and nuclear accumulation of mutant androgen receptors in male transgenic mice. Moreover, leuprorelin treatment reversed the behavioral and histopathological phenotypes that were once caused by transient increases in serum testosterone. Flutamide, an androgen antagonist promoting nuclear translocation of androgen receptors, yielded no therapeutic effect. Leuprorelin thus seems to be a promising candidate for the treatment of SBMA.

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Figure 1: Effects of leuprorelin on symptoms in male AR-97Q mice.
Figure 2: Effects of leuprorelin on mutant androgen receptor expression and neuropathology in male AR-97Q mice.
Figure 3: Effects of testosterone in leuprorelin-treated male AR-97Q mice.
Figure 4: Reversal of symptoms and pathological findings with leuprorelin treatment.
Figure 5: Effects of flutamide on the symptoms of male AR-97Q mice.
Figure 6: Effects of flutamide on mutant androgen receptor expression and neuropathology in male AR-97Q mice.

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References

  1. Kennedy, W.R., Alter, M. & Sung, J.H. Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 18, 671–680 (1968).

    Article  CAS  Google Scholar 

  2. Sobue, G. et al. X-linked recessive bulbospinal neuronopathy. A clinicopathological study. Brain 112, 209–232 (1989).

    Article  Google Scholar 

  3. Sobue, G. et al. Subclinical phenotypic expressions in heterozygous females of X-linked recessive bulbospinal neuronopathy. J. Neurol. Sci. 117, 74–78 (1993).

    Article  CAS  Google Scholar 

  4. Mariotti, C. et al. Phenotypic manifestations associated with CAG-repeat expansion in the androgen receptor gene in male patients and heterozygous females: a clinical and molecular study of 30 families. Neuromuscul. Disord. 10, 391–397 (2000).

    Article  CAS  Google Scholar 

  5. Schmidt, B.J., Greenberg, C.R., Allingham-Hawkins, D.J. & Spriggsm E.L. Expression of X-linked bulbospinal muscular atrophy (Kennedy disease) in two homozygous women. Neurology 59, 770–772 (2002).

    Article  Google Scholar 

  6. La Spada, A.R., Wilson, E.M., Lubahn, D.B., Harding, A.E. & Fischbeck, K.H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).

    Article  CAS  Google Scholar 

  7. Tanaka, F. et al. Founder effect in spinal and bulbar muscular atrophy (SBMA). Hum. Mol. Genet. 5, 1253–1257 (1996).

    Article  CAS  Google Scholar 

  8. Doyu, M. et al. Severity of X-linked recessive bulbospinal neuronopathy correlates with size of the tandem CAG repeat in androgen receptor gene. Ann. Neurol. 32, 707–710 (1992).

    Article  CAS  Google Scholar 

  9. Igarashi, S. et al. Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy. Neurology 42, 2300–2302 (1992).

    Article  CAS  Google Scholar 

  10. Zoghbi, H.Y. & Orr, H.T. Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217–247 (2000).

    Article  CAS  Google Scholar 

  11. Li, M. et al. Nuclear inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy. Ann. Neurol. 44, 249–254 (1998).

    Article  CAS  Google Scholar 

  12. Li, M. et al. Nonneural nuclear inclusions of androgen receptor protein in spinal and bulbar muscular atrophy. Am. J. Pathol. 153, 695–701 (1998).

    Article  CAS  Google Scholar 

  13. Ross, C.A. Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders. Neuron 35, 819–822 (2002).

    Article  CAS  Google Scholar 

  14. Taylor, J.P. & Fischbeck, K.H. Altered acetylation in polyglutamine disease: an opportunity for therapeutic intervention? Trends Mol. Med. 8, 195–197 (2002).

    Article  CAS  Google Scholar 

  15. Katsuno, M. et al. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35, 843–854 (2002).

    Article  CAS  Google Scholar 

  16. Huggins, C. & Hodges, C.V. Studies on prostatic cancer. I. The effects of castration, of estrogen and of androgen injection on serum phosphates in metastatic carcinoma of the prostate. Cancer Res. 1, 293–297 (1941).

    CAS  Google Scholar 

  17. Labrie, F. Mechanism of action and pure antiandrogenic properties of flutamide. Cancer 72 (suppl. 12), 3816–3827 (1993).

    Article  CAS  Google Scholar 

  18. Yamamoto, A., Lucas, J.J. & Hen R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57–66 (2000).

    Article  CAS  Google Scholar 

  19. Kemppainen, J.A. & Wilson, E.M. Agonist and antagonist activities of hydroxyflutamide and casodex relate to androgen receptor stabilization. Urology 48, 157–163 (1996).

    Article  CAS  Google Scholar 

  20. Lu, S., Simon, N.G., Wang, Y. & Hu, S. Neural androgen receptor regulation: effects of androgen and antiandrogen. J. Neurobiol. 41, 505–512 (1999).

    Article  CAS  Google Scholar 

  21. Tomura, A. et al. The subnuclear three-dimensional image analysis of androgen receptor fused to green fluorescence protein. J. Biol. Chem. 276, 28395–28401 (2001).

    Article  CAS  Google Scholar 

  22. Walcott, J.L. & Merry, D.E. Ligand promotes intranuclear inclusions in a novel cell model of spinal and bulbar muscular atrophy. J. Biol. Chem. 277, 50855–50859 (2002).

    Article  CAS  Google Scholar 

  23. Takeyama, K. et al. Androgen-dependent neurodegeneration by polyglutamine-expanded human androgen receptor in Drosophila. Neuron 35, 855–864 (2002).

    Article  CAS  Google Scholar 

  24. Fischbeck, K.H., Lieberman, A., Bailey, C.K., Abel, A. & Merry, D.E. Androgen receptor mutation in Kennedy's disease. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 354, 1075–1078 (1999).

    Article  CAS  Google Scholar 

  25. Lieberman, A.P., Harmison, G., Strand, A.D., Olson, J.M. & Fischbeck, K.H. Altered transcriptional regulation in cells expressing the expanded polyglutamine androgen receptor. Hum. Mol. Genet. 11, 1967–1976 (2002).

    Article  CAS  Google Scholar 

  26. Gottlieb, .B, Pinsky, L., Beitel, L.K. & Trifiro, M. Androgen insensitivity. Am. J. Med. Genet. 89, 210–217 (1999).

    Article  CAS  Google Scholar 

  27. MacLean, H.E., Warne, G.L. & Zajac, J.D. Defects of androgen receptor function: from sex reversal to motor neurone disease. Mol. Cell. Endocrinol. 112, 133–141 (1995).

    Article  CAS  Google Scholar 

  28. Kobayashi, Y. et al. Chaperones Hsp70 and Hsp40 suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract. J. Biol. Chem. 275, 8772–8778 (2000).

    Article  CAS  Google Scholar 

  29. Adachi, H et al. HSP70 chaperone over-expression ameliorates phenotypes of the SBMA transgenic mouse model by reducing nuclear-localized mutant AR protein. J. Neurosci. 23, 2203–2211 (2003).

    Article  CAS  Google Scholar 

  30. Cummings, C..J, et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat. Genet. 19, 148–154 (1998).

    Article  CAS  Google Scholar 

  31. Cummings, C.J. et al. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum. Mol. Genet. 10, 1511–1518 (2001).

    Article  CAS  Google Scholar 

  32. McCampbell, A. et al. Histone deacetylase inhibitors reduce polyglutamine toxicity. Proc. Natl. Acad. Sci. USA 98, 15179–15184 (2001).

    Article  CAS  Google Scholar 

  33. Steffan, J.S. et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739–743 (2001).

    Article  CAS  Google Scholar 

  34. Hockly, 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).

    Article  CAS  Google Scholar 

  35. Kobayashi, Y. et al. 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, 145–150 (1998).

    Article  CAS  Google Scholar 

  36. Niwa, H., Yamamura, K. & Miyazaki, J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108, 193–199 (1991).

    Article  CAS  Google Scholar 

  37. Adachi, H. 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).

    Article  CAS  Google Scholar 

  38. Luo, S. et al. Daily dosing with flutamide or Casodex exerts maximal antiandrogenic activity. Urology 50, 913–919 (1997).

    Article  CAS  Google Scholar 

  39. Trottier, Y. et al. Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias. Nature 378, 403–406 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. Miyazaki for providing the pCAGGS vector. This work was supported by a Center-of-Excellence grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan; by grants from the Ministry of Health, Labour and Welfare, Japan; by a grant from Naito Foundation; and by a grant from Kanae Foundation.

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

    Masahisa Katsuno, Hiroaki Adachi, Manabu Doyu, Makoto Minamiyama, Chen Sang, Yasushi Kobayashi, Akira Inukai & Gen Sobue

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  1. Masahisa Katsuno
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Correspondence to Gen Sobue.

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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 9, 768–773 (2003). https://doi.org/10.1038/nm878

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