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. Thi s disease is unusual among the polyglutamine diseases in that it involves l ower motor and sensory neurons, with relative sparing of other brain struct ures, We describe the development of transgenic mice, created with a trunca ted, highly expanded androgen receptor driven by the neurofilament light ch ain promoter, which develop many of the motor symptoms of SBMA. In addition , transgenic mice created with the prion protein promoter develop widesprea d neurologic disease, reminiscent of juvenile forms of other polyglutamine diseases, Thus, in these experiments, the distribution of neurologic sympto ms depends on the expression level and pattern of the promoter used, rather than on specific characteristics of androgen receptor metabolism or functi on, The transgenic mice described here develop neuronal Intranuclear inclus ions (NIIs), a hallmark of SBMA and the other polyglutamine diseases. We ha ve shown these inclusions to be ubiquitinated and to sequester molecular ch aperones, components of the 26S proteasome and the transcriptional activato r CREB-binding protein, Apart from the presence of NIIs, evidence of neurop athology or neurogenic muscle atrophy was absent, suggesting that the neuro logic phenotypes observed in these mice were the result of neuronal dysfunc tion rather than neuronal degeneration. These mice will provide a useful re source for characterizing specific aspects of motor neuron dysfunction, and for testing therapeutic strategies for this and other polyglutamine diseas es.