Polyglutamine androgen receptor: from post-translational modifications to therapeutic development for spinobulbar muscular atrophy

February 3, 2012
2:30 p.m.

Spinobulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is a genetically inherited and X-linked motor neuron disease characterized by the loss of lower motor neurons and skeletal muscle weakness, fasciculation, and atrophy.  SBMA is caused by the expansion of a polyglutamine tract in the gene coding for androgen receptor (polyQ-AR). The disease fully manifests only in males, and females do not show any overt phenotype even if homozygous for the mutation. SBMA is triggered by the binding of polyQ-AR to its natural ligands, testosterone and its more potent derivative dihydrotestosterone. Testosterone binding to AR results in the acquisition of numerous post-translational modifications. The toxicity of polyQ proteins is influenced at the post-translational level by several modifications, including phosphorylation. We will present our recent findings, in which we show that phosphorylation of polyQ-AR by Akt reduces ligand-induced nuclear translocation, toxic aggregation, and transactivation. Importantly, we found that phosphorylation blocks ligand binding, thereby preventing toxicity. Activation of Akt by the insulin-like growth factor 1 (IGF-1) specifically in the muscle of SBMA mice increases polyQ-AR phosphorylation and leads to protein degradation through the proteasome. Importantly, genetic and pharmacologic manipulation of IGF-1 in SBMA muscle results in amelioration of muscle and spinal cord pathology, reduced motor dysfunction, and increased survival. Our results indicate that the genetic interaction between androgen and insulin pathways in muscle is critical in SBMA pathogenesis.