Many neurodegenerative diseases, including spinal and bulbar muscular atrophy (SBMA) and ALS, result from protein misfolding and accumulation due to a variety of both genetic and environmental causes. SBMA is an adult-onset neuromuscular disease that is caused by polyglutamine expansion within the androgen receptor (AR);it is related mechanistically to other neurodegenerative diseases caused by polyglutamine expansion. Although the precise pathway leading to neuronal dysfunction and death is unknown, the evaluation of transgenic mouse and cell models of these diseases have yielded many mechanistic clues. Our transgenic cell and mouse models of SBMA reproduce the proximate events of polyglutamine-dependent proteolysis and aggregation, making these models highly useful for the analysis of novel therapeutic avenues that affect these upstream events. SBMA stands apart from other polyglutamine diseases in that its onset and progression are androgen- dependent. Our preliminary studies in our cell models of SBMA indicate that a structural change in the AR that occurs upon androgen binding and that involves an interdomain interaction between the amino- (N-) and carboxyl- (C-) terminal regions is required for mutant AR aggregation and toxicity. Our long-term objectives are to use our transgenic mouse and cell models to evaluate the therapeutic efficacy of novel AR ligands that prevent the AR N/C interaction. We predict that these studies will reveal the details of which of these ligands is most effective and allow us to further develop this subclass of ligands for therapeutic intervention. To reach these goals, we propose two specific aims: 1) To evaluate the efficacy of SARMs that prevent the N/C interaction in modulating AR aggregation and toxicity in two cell models of SBMA, and to evaluate the transcriptional function of the mutant AR upon SARM binding;2) To carry out preclinical testing of the most effective SARMs in our transgenic mouse model of SBMA. We anticipate that results from these studies will lead us to new therapies for SBMA and will open a novel investigational door for other polyglutamine diseases as well.
Polyglutamine diseases represent a larger 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 are developing a therapeutic strategy designed to prevent the abnormal folding and accumulation of mutant protein, which represents an upstream event in the pathogenic pathway. The studies proposed here will test novel therapeutic compounds that bind to the mutant protein, allow its normal function, but prevent the formation of a toxic conformation;this strategy, if successful, should also be relevant to other neurodegenerative diseases.