ABSTRACT Spinal and bulbar muscular atrophy (SBMA) is a degenerative disorder of the neuromuscular system caused by a CAG/glutamine tract expansion in the androgen receptor (AR) gene. The polyglutamine AR (polyQ AR) undergoes hormone-dependent nuclear translocation and unfolding, steps that are essential to toxicity and to the development of progressive muscle weakness in men. Although it was long considered that lower motor neurons are the primary targets of degeneration in SBMA, recent studies from our laboratory and others have established the importance of peripheral polyQ AR expression in disease. This work highlights a central contribution of polyQ AR expression in skeletal muscle to weakness and atrophy. Based on these findings, we have developed an innovative model of SBMA pathogenesis in which degeneration of the neuromuscular system begins with toxic effects in skeletal muscle and progresses over time to involve spinal motor neuron degeneration. Here, we propose to test this model of disease pathogenesis in gene targeted mice (AR113Q mice) expressing polyQ AR at endogenous levels and in appropriate cell types. The objective of this application is to experimentally test our novel model of disease pathogenesis. This model forms our central hypothesis and is supported by a rigorous foundation of published and preliminary data. Here, we will use two complementary approaches to test our central hypothesis: First, we will use antisense oligonucleotides (ASOs) to knock-down expression of polyQ AR selectively in peripheral tissues or CNS of symptomatic AR113Q mice and determine effects on late onset motor neuron degeneration. Second, we will restore function of a critical transcriptional regulator in skeletal muscle that contributes to SBMA skeletal muscle atrophy and then determine the extent to which this influences the AR113Q phenotype, including motor neuron degeneration. These aims will be complemented by studies designed to leverage the endogenous cellular machinery that regulates polyQ AR degradation in order to eliminate proteotoxicity in disease relevant human cells. We will use biochemical, genetic, and histological assays to establish beneficial effects of AR targeted ASOs administered to symptomatic AR113Q mice (Aim 1), determine the extent to which increased MEF2 function rescues the AR113Q phenotype (Aim 2), and establish effects of targeting the Hsp90/Hsp70 chaperone machinery in SBMA models (Aim 3). These studies are expected to experimentally test our proposed model of disease pathogenesis and provide a strong foundation for developing targeted therapies to treat SBMA patients.

Relevance to public health: The relevance of the proposed studies to public health is that they will define mechanisms triggering neuromuscular degeneration in SBMA. This work is expected to test a novel model of disease pathogenesis, thereby setting the stage for future discovery efforts to develop new therapeutic strategies.