Spinal Bulbar Muscular Atrophy (SBMA) is a motor neuron disease, typically viewed as neurogenic in origin, meaning triggered by problems that begin in motoneurons. SBMA is caused by a mutation in the androgen receptor (AR) gene involving an expansion of CAG repeats coding for glutamines in the protein. We created a transgenic (tg) mouse line in which a rat AR cDNA with a wildtype (wt) number of glutamine residues (22) is expressed exclusively in skeletal muscle fibers at very high levels. Most notably, only untreated transgenic male mice and not female mice develop a severe neuromuscular phenotype resembling SBMA, paralleling the prominent sex bias of SBMA in humans. This phenotype is characterized by an androgen-dependent loss in motor function, loss of muscle fibers and motor axons, and changes in muscle gene expression consistent with denervation. In contrast, tg females appear healthy until treated with testosterone (T) as adults, again demonstrating the androgen-dependence of the disease phenotype in our mouse model. As little as 3 days of T treatment induces a marked loss of motor function in tg females, and by 10 days, tg females look like diseased males, including having kyphosis and motor dysfunction. Furthermore, flutamide, an AR antagonist, successfully prevents the rapid demise of T treated tg females and may be a potential therapeutic for treating SBMA. Finally, I show that male mice having functional ARs only in muscle fibers and not elsewhere also exhibit an androgen-dependent motor disease phenotype. These results indicate that severe neuromuscular dysfunction mimicking SBMA can be induced by over-expression of the wt AR exclusively in muscle fibers. Results from both tg males and females suggest that ligand activation of wt ARs in muscle fibers is sufficient to trigger motor neuron disease, suggesting that SBMA and possibly other motor neuron diseases may in fact be myogenic and that muscles offer a new and accessible target for therapeutics.Spinal Bulbar Muscular Atrophy (SBMA) is a motor neuron disease, typically viewed as neurogenic in origin, meaning triggered by problems that begin in motoneurons.
|Title||:||When Androgen Receptors Go Awry: Muscle Specific Expression Triggers Spinal Bulbar Muscular Atrophy (SBMA).|
|Author||:||Jamie Ann Johansen|
|Publisher||:||ProQuest - 2008|