Date of Award
Doctor of Philosophy (PhD)
J. Paul Taylor
Spinobulbar muscular atrophy (SBMA) is a progressive, late-onset disease characterized by degeneration of motor neurons in the brainstem and spinal cord. The disease is caused by expansion of a polyglutamine tract in the androgen receptor (AR) and is dependent on exposure to AR ligand. The expanded polyglutamine tract confers toxic function to the protein through unknown mechanisms, although the ligand-dependent nature of SBMA suggests that the mechanism of pathogenesis may be tied to ligand-dependent alterations in AR function. However, whether toxicity is mediated by native AR function or a novel AR function is unknown. We systematically investigated ligand-dependent modifications of AR in a Drosophila model of SBMA. We demonstrate in vivo that nuclear translocation of mutant AR is necessary but not sufficient for toxicity and that DNA binding by AR is necessary for toxicity. Mutagenesis studies demonstrated that a functional AF-2 domain is essential for toxicity, a finding corroborated by a genetic screen that identified AF-2 interactors as dominant modifiers of degeneration. As proof of this principle, we perform epistasis experiments using the AR coregulator limpet, which we find modifies polyglutamine-expanded AR toxicity in an AF-2-dependent manner. In addition, we use expression profiling to examine the molecular phenotype of polyglutamine-expanded AR degeneration, revealing that expression of wild-type AR results in a molecular phenotype that is very similar to that caused by polyglutamine-expanded AR. These findings suggest that expanded-polyglutamine AR toxicity may be mediated by amplification of normal function, a mechanism that may be broadly applicable to other polyglutamine diseases.
Nedelsky, Natalia B., "Native Functions of the Androgen Receptor are Essential to Pathogenesis in a Drosophila Model of Spinobulbar Muscular Atrophy" (2010). Publicly Accessible Penn Dissertations. Paper 463.