Spinal-bulbar muscular atrophy (SBMA) is caused by mutation in the gene for the androgen receptor (AR). It causes slowly progressive loss of motor neurons (the nerve cells that control voluntary movement), especially those controlling facial and swallowing muscles, and the arm and leg muscles, particularly those nearest the center of the body. Symptoms also include hormonal dysfunction related to loss of testosterone activity. The androgen receptor is a protein that binds to the male sex hormone, testosterone. When testosterone binds to the AR, the testosterone/AR complex can enter the cell nucleus. Like many other hormones, testosterone exerts its effects by controlling the expression of a range of genes in the nucleus, and the AR is critical for this purpose. SBMA is “X-linked”, which is to say it is usually inherited by males, who inherit the mutation from their mother.
The mutation that causes SBMA is called a trinucleotide repeat expansion. Genes are made of DNA; DNA is composed of subunits, called nucleotides, strung together. The AR gene includes a segment of nucleotides in which the three DNA “letters” C-A-G repeat multiple times. The normal gene contains up to CAG 36 repeats. In people with SBMA, the AR gene contains 38 or more CAG repeats. This trinucleotide CAG sequence causes the amino acid glutamine to be incorporated into the AR protein. When the mutant gene is translated, the resulting protein contains too many glutamine amino acids. The extra glutamines causes the protein to misfold, taking on the wrong shape and making the resulting protein molecule “sticky,” causing it to clump together. It is not clear how this leads to loss of motor neurons, and discovering the steps in the disease pathogenesis is a major focus of research.
Studies in the mouse model of SBMA have indicated that the AR must enter the nucleus in order to exert its toxic effects. Thus, preventing nuclear entry is a rational therapeutic strategy. Other strategies include inhibiting or correcting the effects of the AR/testosterone complex on its target genes; reducing testosterone or reducing its ability to bind to the AR; increasing breakdown of the misfolded AR protein; and reducing the damage to those cells and cellular structures most severely affected by the disease process.