Targeting AR toxicity in SBMA by modulation of USP7 activity.
Summary: PolyQ-expanded androgen receptor-dependent cellular toxicity in the neuromuscular system is a characteristic feature of SBMA pathogenesis, although the molecular mechanisms for these effects are poorly understood. However, because cellular toxicity in SBMA is likely to arise, at least in part, from the polyQ-expanded-dependent dysregulation of protein-protein interactions that sustain normal cellular function, we reasoned that identification of such dysregulated interactions might help reveal potential therapeutic targets for disease modification. Therefore, as part of a KDA-funded project (2014), we used a quantitative proteomics approach and identified a deubiquitinating enzyme, USP7, that preferentially interacts with polyQ-expanded AR and contributes to toxicity. In fact, we have demonstrated that not only does partial knockdown of USP7 protein expression decrease mutant AR-dependent aggregation and dihydrotestosterone-dependent cytotoxicity, but also that overexpression of the protein aggravates these cellular effects. These results establish the need for further investigation into the role of the deubiquitinating function of USP7 in SBMA pathogenesis. The objective of this -research is to investigate the functional consequence of pharmacological inhibition of USP7 deubiquitinase activity in cellular and mouse models of SBMA. These studies will extend our previous KDA-funded proteomics work and, if successful, will establish the validity of inhibition of USP7 activity as a therapeutic approach for the treatment of SBMA.
