Spinal and bulbar muscular atrophy (SBMA) is one of nine polyglutamine diseases and is caused by expansion of CAG in the androgen receptor (AR) gene. Despite the widespread distribution of polyglutamine proteins in the central nervous system, specific populations of neurons are vulnerable in each disease, suggesting that selective neuronal vulnerability arises from intrinsic properties of the mutant proteins. The central hypothesis of this proposal, based on preliminary data, is that neurotoxicity is influenced by protein context, aberrant protein-protein interactions and cell context. The applicant will test this hypothesis at the Italian Institute of Technology (Genoa, Italy) in collaboration with the National Institutes of Health (MD, USA), from where she returns, and the St Jude Children’s Hospital (TN, USA), by pursuing the following Aims: 1) To characterize the impact of phosphorylation on mutant AR toxicity. The applicant will test the hypothesis that protein kinase A reduces mutant AR toxicity by a mechanism that involves modification of mutant protein phosphorylation in SBMA cells. 2) To characterize the role of FOXO in polyglutamine disease. The applicant will test the hypothesis that IGF-1/Akt signalling promotes neuronal survival through inhibition of FOXO in mouse models of SBMA. 3) To determine the impact of tissue-specificity of mutant protein expression. The applicant will test the hypothesis that expression of the disease protein in a tissue-specific fashion influences SBMA pathogenesis. The applicant will use the LoxP-Cre system. Transgenic LoxP-AR mice have been generated in Memphis. This collaboraive project between the host Institution, the Italian Institute of Technology and the Institution from which the fellow returns, NIH USA, and the St Jude Children Hospital, USA, is expected to provide novel insights into the mechanisms of disease pathogenesis in neurodegenerative diseases and to contribute to the transfer of knowldge to Europe.