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. Our long-term objectives are to use these models to develop a mechanistic understanding of steps in SBMA pathogenesis that occur in response to hormone binding and to develop therapeutic approaches based on that understanding. Our previous studies revealed that a specific conformational state of the AR that occurs upon hormone binding, the N/C interaction, is required for its aggregation and toxicity; inhibition of the N/C interaction is protective in both in vitro and in vivo models. Moreover, we found that Ser-16 phosphorylation is required for this protection. We propose in this application to further understand the mechanism underlying the role of both the AR N/C interaction and Ser-16 phosphorylation in disease. In addition, we propose to screen selective AR modulators (SARMs) that prevent the AR N/C interaction for their effects on SBMA pathogenesis, both in vitro and in vivo. 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.

Public Health Relevance

Spinal and bulbar muscular atrophy (SBMA) is one of 9 polyglutamine diseases, which are themselves part of a large family of neurodegenerative diseases characterized by protein misfolding and accumulation; these diseases include Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). We have identified a structural characteristic of the mutant androgen receptor (AR), which causes SBMA, that plays an important role in disease and represents a druggable therapeutic target. The studies proposed here represent powerful approaches to determine the mechanistic basis for the role of the AR N/C interaction in SBMA and to test selective AR modulators (SARMs) that target this feature, both in vitro and in vivo.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Gubitz, Amelie
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Thomas Jefferson University
Schools of Medicine
United States
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