Abstract
Spinal and bulbar muscular atrophy (SBMA) is caused by the polyglutamine androgen receptor (polyQ-AR), a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC) transgenic mice that express the full-length polyQ-AR and display androgen-dependent weakness, muscle atrophy, and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery but not the CNS after subcutaneous administration. Suppression of polyQ-AR in the periphery rescued deficits in muscle weight, fiber size, and grip strength, reversed changes in muscle gene expression, and extended the lifespan of mutant males. We conclude that polyQ-AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients.
Highlights
Spinal and bulbar muscular atrophy (SBMA) is one of nine untreatable diseases caused by CAG/glutamine tract expansions
The mutation leads to a partial loss of transactivation function (Chamberlain et al, 1994; Irvine et al, 2000; KazemiEsfarjani et al, 1995; Lieberman et al, 2002; Mhatre et al, 1993), and while this may contribute to features of androgen insensitivity, neuromuscular degeneration is mediated by a toxic gain of function conferred by protein unfolding
We conclude that polyQ androgen receptor (AR) expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients
Summary
Spinal and bulbar muscular atrophy (SBMA) is one of nine untreatable diseases caused by CAG/glutamine tract expansions. Clinical onset occurs in adolescence to adulthood and is characterized initially by muscle cramps and elevated serum creatine kinase (Katsuno et al., 2006b; Sperfeld et al, 2002) These myopathic features commonly precede muscle weakness, which inevitably develops as the disease progresses and is most severe in the proximal limb and bulbar muscles. Binding of testosterone or dihydrotestosterone to the polyQ AR promotes ligand-dependent unfolding and nuclear translocation of the mutant protein (Katsuno et al, 2002; Takeyama et al, 2002). These steps are required for pathogenesis and underlie the occurrence of disease only in men. As the Hsp90-based chaperone machinery controls proteostasis of the AR (Morishima et al, 2008; Thomas et al, 2004; Thomas et al, 2006; Wang et al, 2010), genetic and pharmacological approaches to promote Hsp70-dependent ubiquitination have been shown to facilitate degradation of the mutant protein (Wang et al, 2013)
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