SBMA is a
hereditary neurodegenerative disease caused by expansion of a trinucleotide CAG repeat, which encodes the
polyglutamine tract, in the first exon of the
androgen receptor (AR) gene. The phenotypic difference with gender, which is a specific feature of SBMA, has been recapitulated in a transgenic mouse model of SBMA expressing the full-length human AR containing 97 CAGs under the control of a cytomegalovirus enhancer and a chicken
beta-actin promoter (AR-97Q). Affected SBMA mice demonstrate small body size, short life span, progressive
muscle atrophy and weakness as well as reduced cage activity, all of which are markedly pronounced and accelerated in the male SBMA mice, but either not observed or far less severe in the female SBMA mice. There is increasing evidence that
testosterone, the
ligand of AR, plays a pivotal role in the neurodegeneration in SBMA. The striking success of
androgen deprivation
therapy in SBMA mouse models has been translated into phase 2, and then phase 3, clinical trials. Moreover, animal studies have also been revealing key molecules in the pathogenesis of SBMA such as
heat shock proteins, transcriptional co-activators, and axon motors, suggesting additional therapeutic targets.