RESEARCH NEWS
NEW MOUSE MODEL FOR SBMA

Seeking to develop treatments for spinal-bulbar muscular atrophy (SBMA), MDA-funded researchers have created a mouse model of the disease.

SBMA, also called Kennedy's disease, is an inherited disorder that attacks nerve cells (neurons) in the spinal cord and brain, with particularly devastating effects on the muscle-controlling nerve cells called motor neurons. The loss of those neurons leads to fasciculations (twitching) and progressive weakness in muscles of the face, neck and shoulders. These symptoms usually manifest themselves between ages 30 and 60.

The disease is caused by a genetic mutation affecting the androgen receptor (AR) — a protein that allows cells to respond to androgen hormones such as testosterone. The mutation, called a trinucleotide repeat expansion, is sort of like a run-on sentence in DNA (the chemical letters that make up our genes). In most people, the phrase "CAG" is repeated about 21 times in the AR gene, but in people with SBMA, it's repeated between 40 and 62 times, researchers have found.

It's not clear how the expanded repeats in AR cause SBMA, but researchers have noted that fragments of the mutant protein accumulate within motor neurons in clumps called aggregates.

In order to better understand the disease and evaluate potential treatments, MDA grantee Diane E. Merry at Thomas Jefferson University in Philadelphia has spent years trying to reproduce the disease-causing AR mutations in mice. But for some reason, mice with the maximum number of repeats seen in the human AR gene don't develop SBMA.

Now, with MDA backing, Merry and her colleagues have made a severely mutated AR gene that produces only a small fragment of the AR protein (similar to the kind found in aggregates), and contains 112 repeats. When Merry "turns on" this gene in the nervous system of mice, the mice develop signs and symptoms of SBMA.

That study, which appears in the Jan. 15 issue of Human Molecular Genetics, is the first published scientific report of a mouse model for SBMA.

Merry and her team plan to use their new mouse model to test potential SBMA treatments aimed at reducing the production of abnormal AR protein.