Monash IRD creates mouse model for neuro disease

Researchers at the Monash Institute of Reproduction and Development have succeeded in creating a transgenic mouse model for Kennedy disease, a neurodegenerative disease that affects approximately 1 in 50,000 men.

The transgenic mouse, which is described in the current issue of Human Molecular Genetics, will allow the Monash team headed by Dr John Morrison to determine how the disease develops and examine possible therapeutic approaches.

"By creating mice that develop this Kennedy disease it's possible to more rapidly gain an understanding of how these diseases occur," Morrison said.

He explained that the disease was caused by a mutation resulting in a poly-glutamine repeat or expansion in the androgen receptor protein. It is a member of the poly-glutamine repeat disease family which includes Huntington's disease and other neurodegenerative diseases.

The disease, which in humans is X-linked, generally develops in men in their 40s, and leads to loss of motor neurones, muscular atrophy and testicular pathology.

The mouse model is interesting for a number of reasons, according to Morrison. The mice have most of the symptoms of the human disease, including muscle weakness and infertility. However, in mice the disease also occurs in females, but progresses more slowly, which may provide an insight into the disease process.

Morrison believes that testosterone, which binds to the androgen receptor, may play an important role in controlling the disease progression. Females have significantly less circulating testosterone, and this may influence the rate of neurodegeneration.

In addition, while the androgen receptor is widely expressed in both males and females, the motor neurons appear to be significantly affected, suggested that something about these cells makes them more susceptible. There is also evidence that cells in the testes are affected, which may explain the fertility problems linked to the condition.

"We'd like to pursue the hypothesis that testosterone is causing the disease. There are a whole lot of drugs that affect testosterone that we can use," explained Morrison. "We are very interested in pursuing what is missing in motor neurons to see what is causing the disease to develop."

Morrison hopes that the research will eventually lead to a treatment for Kennedy disease.

"We know a lot about testosterone biology and we know the outcomes of manipulating that biology. If the mouse model shows that testosterone is involved, then we will have a direct way of treating the disease," he noted.

For more information:

Patrick McManamny et al (2002) "A mouse model of spinal and bulbar muscular atrophy". Human Molecular Genetics 11(18):2103