androgen receptor protein with an expanded polyglutamine tract called polyQ-AR. The repeat expansion likely causes a toxic gain of function in the receptor protein, since loss of receptor function in androgen insensitivity syndrome does not cause motor neuron degeneration. Multiple studies have demonstrated that in SBMA, CAG repeat length inversely correlates with the age of symptom onset, but not with the rate of disease progression. Individuals with longer CAG expansions reach ADL milestones earlier (handrail, cane, wheelchair-bound, death) and eventually develop more severe disease manifestations. CAG repeat numbers account for about 60% of the observed variation in motor disability, indicating other factors may play important roles disease progression. The mechanisms which lead to neurodegeneration in SBMA are not fully understood. In SBMA, polyQ-AR misfolds and aggregates, leading to formation of nuclear inclusions (NIs) and diffuse accumulation of AR in the nucleus. This aggregation of the mutant protein is dependent on the presence of testosterone, the ligand for the androgen receptor. Female carriers of SBMA express polyQ-AR are generally asymptomatic or manifest only mild symptoms, due to lower levels of testosterone. Similarly, in animal models of SBMA castration dramatically reduces disease phenotype. Toxicity is believed to occur through multiple cellular mechanisms including transcriptional dysregulation, mitochondrial dysfunction, disruption of protein homeostasis and cellular signaling pathways, as well as autophagy. SBMA is member of a group of diseases caused by polyglutamine expansion, including Huntington's disease and six types of spinocerebellar ataxia. Common characteristics of polyglutamine (or polyQ) diseases is the accumulation of polyQ proteins and the progressive degeneration of nerve cells, usually affecting people later in life. However different polyQ-containing proteins damage different subsets of neurons, leading to different symptoms. Role of skeletal muscle in disease pathophysiology SBMA has traditionally been considered primarily a disease of the motor neuron. Motor neurons degeneration is seen in the anterior horn of the spinal cord and brainstem, and electrophysiology studies show evidence of motor neuron dysfunction. However, several studies have suggested skeletal muscle plays an important role in SBMA pathophysiology. Myogenic abnormalities in patient muscle include atrophic and morphologically abnormal muscle fibers, fiber-type grouping, and centralized nuclei. Serum creatine kinase (CK) levels are much higher than would be expected for a purely neurogenic disease. In animal studies, mice which express the polyglutamine androgen receptor in all tissues were shown to develop progressive neuromuscular degeneration mimicking SBMA. However, when the mice were genetically manipulated to express the