Determining the role of AR transcriptional function in SBMA

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Many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and the polyglutamine diseases, result from protein misfolding and accumulation due to a variety of genetic and/or environmental causes. Spinal and bulbar muscular atrophy (SBMA) is an adult-onset, inherited neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR); it is related to other neurodegenerative diseases caused by polyglutamine expansion, including Huntington's disease and several spinocerebellar ataxias. Although the precise pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases has yielded mechanistic insights to disease pathogenesis. SBMA stands apart from other polyglutamine diseases in that its onset and progression are dependent on AR androgenic ligands. Our cell and mouse models of SBMA reproduce the androgen- and polyglutamine-dependent nuclear AR aggregation seen in patients, as well as its consequent toxicity, making these models highly useful for the analysis of the mechanistic basis for upstream events involved in AR toxicity. Previous studies from our group and others revealed that the nuclear localization, N/C interaction, phosphorylation and acetylation of the AR are all required for its aggregation and toxicity. Inhibiting each of these steps through genetic or pharmacological manipulation prevents mutant AR aggregation as well as its toxicity. Notably, inhibition of each of these steps also prevents AR transcriptional activity, highlighting a central question in the understanding of SBMA pathogenesis of the role of AR transcriptional activity in disease. While earlier studies in a Drosophila model of SBMA supported such a role, studies in mammalian systems suggest otherwise. Answering this important question is critical to the development of effective therapies. We propose with this application to answer this central question of the role of AR transcriptional activity in SBMA, through the use of novel cell and animal models, and to use these models to investigate the molecular pathways that mediate disease. We predict that our proposed studies will reveal further details about the role of AR transcriptional activity in disease pathogenesis and provide robust insights into ideal therapeutic directions in SBMA. To achieve these goals, we propose three specific aims: 1) To determine the role of AR DNA binding in disease, in vivo, using novel, genetic knock-in mouse models of SBMA; 2) To evaluate the role of DNA binding in cell models of SBMA; and 3) To use these models to identify common pathogenic pathways through transcriptional profiling and quantitative analysis of mutant AR-interacting proteins. We anticipate that results from these studies will lead us to a new understanding of the molecular pathogenesis of SBMA and enhance our development of new therapies for SBMA.