Altered Trafficking and Post-translational Modifications of the Polyglutamine-Expanded Androgen Receptor Contribute to Toxicity in Spinal and Bulbar Muscular Atrophy

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a polyglutamine (polyQ) expansion in the androgen receptor (AR). Despite the fact that the monogenic cause of SBMA has been known for nearly three decades, there is no effective treatment for this disease, underscoring the complexity of the pathomechanisms that lead to a loss of motor neurons and muscle in SBMA patients. In the present work, we demonstrate that altered trafficking and post-translational modifications of the polyQ-expanded AR contribute to toxicity in SBMA, thus revealing new pathways that may be targeted therapeutically while advancing our understanding of the molecular mechanisms that play a role in disease. First, given prior evidence highlighting the importance of AR nuclear localization in SBMA pathogenesis, we sought to determine the role of AR nuclear export in SBMA. We found that the nuclear export of polyQ-expanded AR is impaired, and that promoting AR export with an exogenous nuclear export signal substantially reduces its aggregation and toxicity. Moreover, we show that these protective effects are conferred by destabilization of the mutant protein due to proteasomal degradation of the exported, cytoplasmic AR. Despite evidence that global disruption of nucleo/cytoplasmic transport occurs in other neurodegenerative disorders, our data suggest that AR-specific mechanisms are likely responsible for the impaired nuclear export of polyQ-expanded AR. In a second study, we built upon previous data which demonstrated that decreasing AR acetylation, either by genetic mutation of three lysine residues within the hinge region of the AR, or by overexpression of the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuin 1 (SIRT1), reduces its aggregation and toxicity. Here, we show that genetically blocking the acetylation of polyQ-expanded AR in vivo substantially decreases its stability in the presence of hormone and delays disease onset in transgenic mouse model of SBMA. Finally, we treated post-symptomatic transgenic SBMA mice with the NAD+ precursor nicotinamide riboside (NR) with the aim of increasing NAD+ levels in these mice, thereby activating SIRT1. We found that NR supplementation was unable to alter disease progression despite increasing NAD+ content in the central nervous system (CNS). Further analyses revealed disruptions in energy metabolism in the muscle, but not in the CNS of transgenic mice, providing new insights into the differential metabolic disruption that occurs in the CNS versus the muscle of a mouse model of SBMA. Moreover, this demonstrates that high expression of mutant AR in the CNS is capable of driving metabolic dysfunction in the muscle. It remains to be determined which direction(s) of study will ultimately lead to a treatment for SBMA; thus, further exploration in all directions is imperative. The experiments undertaken here reflect our efforts to advance our understanding of SBMA on multiple fronts, with the ultimate goal of achieving a clinically meaningful outcome in patients