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 transgenic 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 normal AR metabolism that occur upon hormone binding and that are altered by polyglutamine expansion. Our studies in the previous funding period revealed that nuclear localization, the N/C interaction, and acetylation of the AR are all required for its aggregation and toxicity. Moreover, the deacetylase Sirt1 is strongly neuroprotective in cell models of SBMA and this neuroprotection depends upon its ability to deacetylate the mutant AR. In addition, our preliminary studies reveal that DNA binding by the mutant AR is not required for disease. We propose in this renewal application to further investigate the role of DNA binding in SBMA, to determine the role of AR acetylation in vivo, and to identify soluble aggregated AR species that correlate with toxicity in these models. We also propose to investigate the therapeutic potential of activating Sirt1 with small molecule activators We predict that these studies will reveal further details about the step or steps in AR trafficking and metabolism that are derailed by polyglutamine expansion. To achieve these goals, we propose three specific aims: 1) To further evaluate the role of DNA binding in cell and mouse models of SBMA and to use these models to identify common, toxicity-predicting aggregation species;2) To determine the role of AR acetylation in disease, in vivo, and to understand the mechanistic basis for this role;3) To determine the therapeutic potential of Sirt1 activation, using cell and mouse models of SBMA. 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 also include Alzheimer's disease, Huntington's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). We have identified several proximate events in mutant AR metabolism that are involved in its toxicity. The studies proposed here will continue to determine both the role and the mechanistic basis for these events in SBMA, and in so doing, will open new and powerful opportunities for therapeutic development.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-R (04))
Program Officer
Gubitz, Amelie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Thomas Jefferson University
Schools of Medicine
United States
Zip Code
Pratt, William B; Gestwicki, Jason E; Osawa, Yoichi et al. (2015) Targeting Hsp90/Hsp70-based protein quality control for treatment of adult onset neurodegenerative diseases. Annu Rev Pharmacol Toxicol 55:353-71
Pratt, William B; Morishima, Yoshihiro; Gestwicki, Jason E et al. (2014) A model in which heat shock protein 90 targets protein-folding clefts: rationale for a new approach to neuroprotective treatment of protein folding diseases. Exp Biol Med (Maywood) 239:1405-13
Wang, Adrienne M; Miyata, Yoshinari; Klinedinst, Susan et al. (2013) Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat Chem Biol 9:112-8
Cooper, Lori J; Merry, Diane E (2013) Cell biological approaches to investigate polyglutamine-expanded AR metabolism. Methods Mol Biol 1017:241-53