Spinal and bulbar muscular atrophy: ligand-dependent pathogenesis and therapeutic perspectives

J Mol Med (Berl). 2004 May;82(5):298-307. doi: 10.1007/s00109-004-0530-7. Epub 2004 Feb 27.


Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. SBMA exclusively affects males, while females are usually asymptomatic. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract in the first exon of the androgen receptor (AR) gene. The histopathological hallmark is the presence of nuclear inclusions containing mutant truncated ARs with expanded polyQ tracts in the residual motor neurons in the brainstem and spinal cord, as well as in some other visceral organs. The AR ligand, testosterone, accelerates AR dissociation from heat shock proteins and thus its nuclear translocation. Ligand-dependent nuclear accumulation of mutant ARs has been implicated in the pathogenesis of SBMA. Transgenic mice carrying the full-length human AR gene with an expanded polyQ tract demonstrate neuromuscular phenotypes, which are profound in males. Their SBMA-like phenotypes are rescued by castration, and aggravated by testosterone administration. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, inhibits nuclear accumulation of mutant ARs, resulting in the rescue of motor dysfunction in the male transgenic mice. However, flutamide, an androgen antagonist promoting nuclear translocation of the AR, yielded no therapeutic effect. The degradation and cleavage of the AR protein are also influenced by the ligand, contributing to the pathogenesis. Testosterone thus appears to be the key molecule in the pathogenesis of SBMA, as well as main therapeutic target of this disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Disease Models, Animal
  • Humans
  • Leuprolide / therapeutic use
  • Ligands
  • Mice
  • Muscle, Skeletal / pathology
  • Muscular Atrophy, Spinal / drug therapy*
  • Muscular Atrophy, Spinal / etiology
  • Muscular Atrophy, Spinal / genetics*
  • Mutation
  • Peptides / genetics
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism*
  • Spinal Cord / pathology


  • Ligands
  • Peptides
  • Receptors, Androgen
  • polyglutamine
  • Leuprolide