DIFFERENT APPROACHES TO UNDERSTAND AND COUNTERACT SPINAL AND BULBAR MUSCOLAR ATROPHY (SBMA).

Spinal and Bulbar Muscular Atrophy (SBMA), or Kennedy’s disease, is a hereditary neuromuscular disorder that affect only men and is characterized by slowly progressive weakness and atrophy of bulbar, facial, and limb muscles, which are attributable to degeneration of lower motor neurons in the spinal cord and brainstem. The disease is associated with an abnormally expanded CAG repeat in the androgen receptor (AR) gene which results in a longer polyglutamine tract (polyQ) at the N-terminus of the protein. PolyQ tract triggers AR protein misfolding and aggregation and leads to nuclear toxicity and cell death. Many efforts have been done to examine in depth disease pathogenesis and to find strategies to counteract polyQ AR toxicity but many aspects remain incompletely understood. Here we propose three different approaches aimed to contrast the disease. In the first chapter, the anti-androgen Bicalutamide is used in combination with the autophagy activator trehalose, in order to slowdown polyQ AR nuclear translocation and promote its clearance through the cytoplasmic autophagic machinery. The combined treatment strongly reduces polyQ AR protein levels more than the single treatment, thus suggesting an autophagy-mediated clearance as a potential therapeutic strategy. The second chapter focuses on polyQ AR degradation via the ubiquitin-proteasome system (UPS), another major degradation process within the cell. We stabilized Hsp70 in its more active ADP-bound state with the small molecule JG98 and promoted a selective CHIP-mediated ubiquitination and proteasomal degradation of polyQ AR. This confirms the involvement of UPS in SBMA pathogenesis and proposes UPS-mediated degradation of polyQ AR as a possible approach for the treatment of the disease. The last chapter proposes exercise as a non-pharmacological intervention for the treatment of SBMA. Wild type (wt) and AR113Q knock-in mice followed a mild exercise regimen for six weeks, then mice were run to exhaustion and sacrificed. Muscle tissues analysis revealed a significant decrease in type I and II fiber size in the exercised cohort of AR113Q mice compared to control rest mice. These data suggested the existence of muscle abnormalities, possibly exacerbated by exercise, in AR113Q mice.