Investigating the pathogenesis and novel therapeutic approaches in Spinal Bulbar Muscular Atrophy (SBMA). (360G-Wellcome-097264_Z_11_A)

Using the AR100 transgenic mouse model, we will examine the mechanisms that contribute to motor neuron (MN) degeneration in SBMA. AR100 mice have a progressive neuromuscular phenotype accompanied by MN degeneration, and therefore mirror the human disease. Our recent results show that ER stress is present in SBMA MNs, even during embryonic development, suggesting that this mechanism plays a key role in SBMA pathogenesis. In this study we plan to investigate the mechanism by which ER stress results in cell death in SBMA, bytesting 1) whether the MN -specific Fas/NO induced cell death pathway plays a role in SBMA; 2) whether the ER chaperone, Calreticulin (CRT) forms a link between the Fas/NO MN-specific death pathway and ER stress, by testing if changes in CRT levels influence MN vulnerability in SBMA and 3) examining the role of astroglia in SBMA MN degeneration. In addition, in view of our findings that inhibition of ER stress rescues SBMA MN in vitro, we will examine whether this approach is also effective in vivo, by testing the effectof an ER stress inhibitor on disease progression in SBMA mice.