Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder characterized by loss of lower motor neurons and skeletal muscle atrophy. SBMA is caused by CAG expansions (>38 repeats) encoding a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. The disease fully manifests in males, as they have high levels of androgens in the serum. PolyQ-AR is converted to a toxic species upon binding to androgens, testosterone and dihydrotestosterone (DHT). We propose to identify the genes involved in regulating polyQ-AR-mediated toxicity and advance our understanding about the molecular mechanisms underlying SBMA pathogenesis. The main objective of current R21 application is to determine that transcriptional co-regulators of AR mediate the toxic gain-of-function (GOF) of polyQ-AR. We hypothesize that two AR transcription co-regulators, namely protein arginine methyltransferase 6 (PRMT6) and lysine demethylase 1 (LSD1), synergistically cooperate to enhance the toxic GOF of polyQ-AR by changing its transcriptional activity. Our hypothesis is based on our observations that post- translational modifications (phosphorylation and methylation)) of AR are important determinant of the toxicity. We will utilize well-characterized mouse models of SBMA (transgenic AR100Q and knock-in AR113Q mice) that show hormone- and glutamine length?dependent neuromuscular weakness, muscle pathology, and early death. SBMA transgenic and knock-in mice represent good models to study disease pathogenesis and to test pharmacologic intervention. We propose to determine how co-regulators of polyQ-AR function in SBMA. We expect to determine how AR function is regulated in skeletal muscle and dysregulated in SBMA.
The proposed studies are expected to define mechanisms triggering skeletal muscle atrophy in SBMA. We expect to identify novel pathways that significantly contribute to peripheral manifestations of SBMA, thereby novel opening avenues for future discovery efforts to identify and test new therapeutic strategies
