Study of AR transcriptional network in stem cell model of SBMA

X-linked spinal and bulbar muscular atrophy (also known as SBMA or Kennedy's disease) is a rare neuromuscular disorder characterized by adult-onset proximal muscle weakness due to lower motor neuron degeneration. SBMA patients display signs of androgen insensitivity, including gynecomastia, reduced fertility, and testicular atrophy. SBMA, is caused by a CAG- polyglutamine (polyQ) repeat expansion in the androgen receptor (AR) gene and is one member of a family of nine CAG-polyQ repeat disorders that includes Huntington’s disease. For decades, research into the basis of neurological disease focused upon the contribution of neuronal dysfunction to disease pathogenesis. However, over the last ten years, there has been growing evidence in the motor neuron disease field that challenges the prevailing neurocentric theory of the etiology of many neurological diseases. . In the case of SBMA, there is increasing evidence implicating muscle dysfunction as a major component of disease pathogenesis. For therapeutic purposes, however, different groups have demonstrated successful treatments targeting either the skeletal muscles or the central nervous system using different SBMA animal models. Consequently, this lack of consensus in the literature underscores the need for studies of the SBMA AR-mutation on affected cell types - skeletal muscles and motor neurons - in a human background. We hypothesized that polyQ mutation cause disruption in AR binding to the DNA which leads to transcriptional dysregulation that can be pathogenic in motor neurons, skeletal muscles or both. Therefore, the goal of this proposal is to combine AR genome wide occupancy and gene expression data sets generated from SBMA and CRISPR engineered isogenic controls iPSC-derived skeletal muscle and motor neurons. We will then, co-culture the iPSC-derived skeletal muscles with iPSC-derived motor neurons to modulate the AR targets identified in the AR transcriptional network and investigate neuromuscular junctions (NMJ) by analyzing electrophysiological activity of the motor neurons and the skeletal muscles. This work will advance understanding on the molecular mechanisms of human mutant AR to SBMA pathogenesis and evaluate the utility of iPSC-derived skeletal muscles and motor neurons tool to develop SBMA in vitro studies.