Targeting Akt signaling in muscle to identify new therapeutic strategies for spinal and bulbar muscular atrophy

Funding for this project, worth 517,000 euros, was made available under the Telethon-Dulbecco careers program by the Autonomous Province of Trento, which entrusted Fondazione Telethon with the selection.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a genetic disease affecting the motor neuron and skeletal muscle. This disease is caused by a mutation, expansion of a tract in the gene coding for androgen receptor. Androgen receptor is the receptor of male hormone, testosterone. When mutant androgen receptor binds to testosterone, it becomes a toxic species. Our long-term goal is to elucidate why mutant androgen receptor alters motor neuron and muscle function, leading to development of SBMA. In this project, we will test the hypothesis that mutant androgen receptor exerts toxic effects directly on muscle, and this in turn contributes to motor neuron loss. This hypothesis is based on our previous observations, which show that the toxicity of mutant protein can be reduced by activation of a specific signal in muscle, the insulin-like growth factor 1/ Akt pathway. Akt works through activation of several cellular proteins, such as Mdm2 and FOXO3. We propose to test the role of these proteins in disease. To test our hypothesis, we propose to: 1) Express mutant androgen receptor in either muscle or spinal cord to determine the contribution of these tissues to development of disease. To test this hypothesis, we will generate new mouse models of SBMA for expression of the mutant protein in specific tissues. 2) Determine the role of Mdm2 in muscle. We will test whether Mdm2 stimulates the cells to dispose mutant androgen receptor. We will explore the role of Mdm2 in cell and mouse models of SBMA. 3) To elucidate the role of FOXO3, a factor that induces muscle atrophy. The role of FOX3 will be analyzed in cell and mouse models of SBMA. Accomplishment of the research described in this application will allow us to further our knowledge on the mechanisms that lead to development of muscle atrophy in SBMA. With this information in our hands, then we may be able to develop novel and effective therapy for patient treatment.