Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice.

Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor. This disease is unusual among the polyglutamine diseases in that it involves lower motor and sensory neurons, with relative sparing of other brain structures. We describe the development of transgenic mice, created with a truncated, highly expanded androgen receptor driven by the neurofilament light chain promoter, which develop many of the motor symptoms of SBMA. In addition, transgenic mice created with the prion protein promoter develop widespread neurologic disease, reminiscent of juvenile forms of other polyglutamine diseases. Thus, in these experiments, the distribution of neurologic symptoms depends on the expression level and pattern of the promoter used, rather than on specific characteristics of androgen receptor metabolism or function. The transgenic mice described here develop neuronal intranuclear inclusions (NIIs), a hallmark of SBMA and the other polyglutamine diseases. We have shown these inclusions to be ubiquitinated and to sequester molecular chaperones, components of the 26S proteasome and the transcriptional activator CREB-binding protein. Apart from the presence of NIIs, evidence of neuropathology or neurogenic muscle atrophy was absent, suggesting that the neurologic phenotypes observed in these mice were the result of neuronal dysfunction rather than neuronal degeneration. These mice will provide a useful resource for characterizing specific aspects of motor neuron dysfunction, and for testing therapeutic strategies for this and other polyglutamine diseases.