Nuclear mechanisms of polyglutamine toxicity in SBMA

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 DESCRIPTION (provided by applicant): The nature of the nuclear events that transform the mutant androgen receptor (AR) into a toxic species have become a major focus of study in the field of spinal and bulbar muscular atrophy (SBMA) research following the discovery that the onset and progression of disease are hormone-dependent. It is unknown at what point in its metabolism the mutant AR becomes toxic to motor neurons, although work from our lab and others has begun to dissect the pathological pathway. We have recently determined that nuclear localization of the polyglutamine-expanded AR is essential, but not sufficient, for disease. Therefore, hormone-dependent nuclear metabolism of the mutant AR, including post-translational modification, protein-protein interactions and degradation are critical points of interest in determining the events that lead to its toxicity. One post- translational modification f interest is acetylation. Known AR acetylation sites are clustered in the KLKK motif located in the hinge region at positions 630/632/633. Our published studies have revealed that acetylation of these lysine residues is required for both the aggregation and toxicity of polyglutamine-expanded AR in cell models. We propose in this application to determine the role of AR acetylation at these sites in vivo, through the characterization of transgenic mice that express a polyglutamine-expanded AR that is incapable of acetylation at these sites. In addition, through a series of distinct but interconnected studies, we propose to determine the mechanistic basis for the role of AR acetylation in disease. We expect that the results from these studies will allow us to determine whether acetylation of the mutant AR represents a valid drug target for further therapeutic development in SBMA. Moreover, we expect our mechanistic studies to provide answers to central questions regarding the pathogenic mechanisms mediating neurotoxicity in SBMA.