Investigazione del ruolo del recettore degli androgeni nel sistema nervoso centrale in condizioni fisiologiche e patologiche

Androgen Receptor (AR) is a steroid hormone-activated transcription factor located in the cytoplasm in an inactive state. In response to androgen binding, AR shuttles from the cytosol to the nucleus, where it regulates the expression of specific target genes by recognizing and binding specific DNA sequences, termed androgen response elements (ARE), in their promoter and enhancer regions. AR activity is highly regulated by post-translational modification (PTMs), of which the most abundant is phosphorylation. Expansions of CAG triplet, over 38, in the first exon of the AR gene, result in the expression of an AR with an elongated polyglutamine (polyQ) tract. This genetic inherited mutation characterizes the Spinal and Bulbar Muscular Atrophy (SBMA), a neuromuscular disorder. AR is widely expressed throughout the brain, cortex, hippocampus, hypothalamic nuclei, and amygdala. Many studies have been focused on understanding the role of AR in the central nervous system (CNS). However, the AR-driven molecular mechanisms are still largely unknown. The aim of the work is to elucidate the role and the mechanism through which AR is controlled in specific excitable cells, namely neurons, both in physiological and pathological conditions. The working hypothesis has been the direct impinge of neuronal activity on androgen receptor activity modulation. We observed in vitro a rapid phosphorylation patter in AR serine proline (SP) site after neuronal stimulation, suggesting a new role of AR as activity-dependent transcription factor. Moreover, our data suggest that AR can change its subcellular localization in response to androgens and neuronal activity, ultimately modulating the expression of immediate-early and late-response downstream target genes. Our findings suggest a new role for AR in the CNS.