Targeting the interaction of poly-Q expanded AR receptor with pVHL to ameliorate SBMA
Spinal and Bulbar Muscular Atrophy (SBMA) is a neuromuscular disease caused by poly-glutamine (poly-Q) expansions in the androgen receptor (AR), which result, upon ligand binding, in misfolding, aggregation and accumulation. A factor contributing to AR aggregation in SBMA cells is inefficient degradation. AR has been shown to interact with the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that I found to associate with MDM2, protein involved in AR degradation. Here, I propose to elucidate the molecular details of AR/pVHL association and investigate its biological effects to demonstrate the role of pVHL in AR degradation. I will also test PROTAC molecules, already used to induce AR degradation in prostate cancer through pVHL, to study their efficacy in pVHL/MDM2-mediated polyQ-AR degradation in SBMA cells. These experiments may ultimately lead to development of a novel therapeutic strategy for SBMA treatment.
