Insulin-like growth factor 1/Akt and androgen signaling crosstalk in the pathogenesis of spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy is a genetically inherited disease affecting both neurons and muscle. The disease is caused by a mutation in the gene encoding the androgen receptor (AR). AR binds the hormone testosterone, and it is testosterone binding that converts mutant AR into a species toxic to neurons. Upon testosterone binding mutant AR undergoes specific changes, whose functional role in the disease needs to be elucidated. Our long-term goal is to elucidate the mechanism through which testosterone converts mutant AR into a toxic molecule. In this project, we aim at elucidating how one of these modifications, addition of phosphate groups (-PO3), is regulated, and how this modification is coordinated with other modifications induced by binding to testosterone. We will test the hypothesis that this modification of AR is controlled by several factors, including cell type, mutation of AR, testosterone binding, age, and other modifications. This hypothesis is based on our previous findings which show that addition of phosphate groups to AR can reduce testosterone binding and motor neuron loss. Once we clarify how the modification that reduces testosterone binding to the receptor-addition of phosphate groups- is regulated, we will be able to develop intervention targeted to enhance this modification. To this aim, we propose to: 1) Determine how addition of phosphate groups is regulated in a mouse model of SBMA. 2) Determine whether other modifications, such as addition of methyl (-CH3) groups at the same sites where phosphate groups are added, control this process. 3) Determine whether addition of phosphate groups influences modifications of AR that alter its localization inside the cell. This research will help us increase our knowledge on disease etiology and pathogenesis. In detail, it will contribute to clarify how a specific modification of the disease protein is regulated in vivo, and how it is influenced by other modifications. Then, we will use this information to develop novel therapeutic approaches for disease treatment.