X-Linked Spinal and Bulbar Muscular Atrophy: From Clinical Genetic Features and Molecular Pathology to Mechanisms Underlying Disease Toxicity.

Abstract

Spinal and Bulbar Muscular Atrophy (SBMA) is an inherited neuromuscular disorder caused by a CAG-polyglutamine (polyQ) repeat expansion in the androgen receptor (AR) gene. Unlike other polyQ diseases, where the function of the native causative protein is unknown, the biology of AR is well understood, and this knowledge has informed our understanding of how native AR function interfaces with polyQ-AR dysfunction. Furthermore, ligand-dependent activation of AR has been linked to SBMA disease pathogenesis, and has led to a thorough study of androgen-mediated effects on polyQ-AR stability, degradation, and post-translational modifications, as well as their roles in the disease process. Transcriptional dysregulation, proteostasis dysfunction, and mitochondrial abnormalities are central to polyQ-AR neurotoxicity, most likely via a 'change-of-function' mechanism. Intriguingly, recent work has demonstrated a principal role for skeletal muscle in SBMA disease pathogenesis, indicating that polyQ-AR toxicity initiates in skeletal muscle and results in secondary motor neuron demise. The existence of robust animal models for SBMA has permitted a variety of preclinical trials, driven by recent discoveries of altered cellular processes, and some of this preclinical work has led to human clinical trials. In this chapter, we review SBMA clinical features and disease biology, discuss our current understanding of the cellular and molecular basis of SBMA pathogenesis, and highlight ongoing efforts toward therapy development.