X-linked spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration. SBMA is caused by CAG/polyglutamine repeat expansions in the human androgen receptor (AR) gene, and is therefore one of nine neurodegenerative disorders that result from polyglutamine proteins. In our previously funded research grant, we outlined a plan to determine how expansion of the polyglutamine tract in the AR protein causes degeneration of motor neurons in SBMA. By introducing the entire AR gene with 100 CAG repeats on a yeast artificial chromosome (YAC) into mice, we have been successful in recapitulating the SBMA phenotype of neurogenic atrophy and motor neuron loss in a mouse model. Studies of the AR YAC CAG100 (AR100) mouse model indicate that transcription interference with CREB-binding protein (CBP) activation of vascular endothelial growth factor (VEGF) gene expression in the spinal cord may contribute to motor neuronopathy in our SBMA mouse model. We also have created a primary cortical neuron model of AR polyglutamine neurotoxicity that is characterized by neuritic degeneration, caspase activation, and apoptotic cell death that appears dependent upon disinhibition of Bax through inhibition of bcl-2 at the outer mitochondrial membrane. This line of investigation has led us to consider a role for the intrinsic pathway of apoptotic activation in SBMA motor neuron degeneration. Our first two aims will address the role of CBP transactivation interference / VEGF164 down-regulation and of stress kinase-mediated upregulation of BH3-only proteins in AR polyglutamine neurotoxicity. In the third aim, a broader role for AR transcription interference in SBMA motor neuron degeneration will be sought by a microarray expression analysis of gene expression alterations in lumbar spinal cord samples from our SBMA transgenic mouse model. In the final aim, we will attempt to identify non-polyglutamine determinants of AR neurotoxicity in the hope that such studies will clarify the role of AR protein context in SBMA motor neuron degeneration, and will perhaps shed light on molecular pathways likely to be broadly relevant to all motor neuronopathie
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