Characterizing Molecular Modifiers of Pathogenesis in Spinobulbar Muscular Atrophy.

Abstract

Spinobulbar muscular atrophy (SBMA), or Kennedy’s disease, is an inherited neuromuscular disorder caused by a polyglutamine (polyQ) tract expansion in the androgen receptor (AR). This mutation initiates misfolding and aggregation of AR, eliciting toxicity in motor neurons, progressive weakness, and muscle atrophy. PolyQ expansion also compromises the transactivation function of AR in response to androgens, resulting in androgen insensitivity. Although considerable progress has been made in characterizing molecular consequences of the polyQ mutation in SBMA, many aspects of pathogenesis, and in particular the cellular processes that modify disease development, remain incompletely understood. Based on previous work suggesting a pathogenic role of autophagy in SBMA, I use cellular and mouse models to delineate the state of autophagy in SBMA. I show that autophagy is induced in SBMA cells and diseased tissues, and that this is due to depressed mTOR activity. These changes correlate with activity of the transcription factors TFEB and ZKSCAN3, which coordinate expression of autophagy-related genes in SBMA mice and human patients. Furthermore, these alterations in autophagy regulators lead to enhanced responsiveness to stimulation by nutrient deprivation and exercise. These results indicate that dysregulated transcriptional programming promotes induction of autophagy in SBMA and provide evidence for targeting autophagy for therapeutic inhibition. Given the previously established role of small ubiquitin-like modifier (SUMO) on AR function, I characterize a novel knock-in mouse model of SBMA to address the influence of SUMO on SBMA pathogenesis. We introduce mutations that prevent SUMOylation of polyQ AR (AR113Q-KRKR) and demonstrate that, despite unaltered androgen insensitivity and neuromuscular pathology, AR113Q-KRKR mice display a striking extension of lifespan and recovery of exercise tolerance. Complementary expression analysis of the non-SUMOylatable polyQ AR reveals substantial expansion of the receptor’s transactivation activity. These findings suggest that abrogating SUMO modification of polyQ AR mediates amelioration of the SBMA phenotype, in part by improving skeletal muscle physiology. Additionally, these studies not only reveal new insights in the comparative roles of polyQ AR toxicity versus loss of function in affected tissues, but they also establish the benefits of enhancing AR function in SBMA for therapeutic design.