Using cell and animal models to understand pathogenic mechanisms in spinal and bulbar muscular atrophy
Spinal and bulbar muscular atrophy (SBMA) is a late onset neurodegenerative disease caused by a polyglutamine expansion in the androgen receptor. In cell and animal models of SBMA, disease is dependent on hormone and nuclear localization of the AR. However, drugs that lower androgen levels were moderately effective in clinical trials. Moreover, the decreased androgen levels caused decreased mental wellbeing in patients. Therefore, an ideal therapy would prevent the toxicity of expanded-polyglutamine AR while maintaining AR function. A better understanding of disease pathogenesis will enable the development of such targeted therapies. Here, we investigated the role of an interdomain interaction of the AR, between the amino-terminal FxxLF motif and carboxyl-terminal AF-2 domain (N/C interaction), in disease in a mouse model of SBMA. We created transgenic mice that express expanded-polyglutamine AR with a mutation in the FxxLF motif (F23A) to prevent the N/C interaction. We found that preventing the AR N/C interaction delayed disease onset, restored phosphorylation alterations in spinal motor neurons, and reduced aggregation of AR in the ventral horn of the spinal cord compared to male N/C-intact AR-expressing mice. Using cell models of SBMA, we determined that the decreased aggregation and toxicity afforded by the AR F23A mutation were dependent on serine 16 of the AR; mutating this residue abolished the protective effects of the AR F23A. We next sought to examine whether cellular dysfunction was involved in disease pathogenesis. Prior studies in a mouse model of SBMA found substantial behavioral deficits without neuronal loss, suggesting that cellular dysfunction and not cell loss caused behavioral deficits in this mouse model of SBMA. Therefore we examined the neuromuscular junction at a late stage of disease progression for signs of synaptic dysfunction. We found substantial changes in endplate morphology and a decrease in the number of fully innervated endplates in the AR 112Q soleus compared to the non-transgenic soleus, suggesting a possible decrease in synaptic activity. Therefore, pharmacologically increasing synaptic activity could potentially improve patient outcome. Together this thesis identified two specific therapeutic targets for treating SBMA and improving patient outcomes. Further studies should confirm the efficacy of these targets in treating this debilitating neurodegenerative disease.
Zboray, Lori J, "Using cell and animal models to understand pathogenic mechanisms in spinal and bulbar muscular atrophy" (2014). ETD Collection for Thomas Jefferson University. AAI3705054.