INSULIN-LIKE GROWTH FACTOR 1 AND POLYGLUTAMINE EXPANDED ANDROGEN RECEPTOR: INTERACTIONS IN SPINAL AND BULBAR MUSCULAR ATROPHY

Spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease, is a neurodegenerative disorder linked to a polyglutamine expansion in the androgen receptor protein. It is progressive and late onset, and it involves motor neurons death in the brainstem and bulbar region, which results in severe muscular atrophy and fasciculation in the limbs. The disease is ligand dependent, such that only in the presence of testosterone or dy-hydrotestosterone, the androgen receptor’s ligands, the polyglutamine expansion results in neuronal degeneration. Still it is not known why ligand binding results in toxicity for neurons. Here we demonstrate that is possible to modify androgen receptor sensitivity to ligand by phosphorylation at two serines at positions 215 and 792, respectively. Our data show that Akt phosphorylates the polyglutamine expanded androgen receptor at those serines, reduces its affinity to ligand and mitigates ligand dependent toxicity in a cell model of SBMA. Insulin-like growth factor 1 (IGF-I) is the major activator of PI3K/Akt pathway, and it has been proved to play a beneficial role in several neurodegenerative diseases. Here we demonstrate that IGF-I also protects against polyglutamine expanded androgen receptor toxicity, in both an in vitro and in vivo models of SBMA. In particular, we demonstrate that IGF-I reduces accumulation of insoluble aggregates of androgen receptor, and this effect is mediated through phosphorylation at the Akt consensus sites. In our SBMA mouse model, we also demonstrate that selective expression of IGF-I in the skeletal muscle reduces insoluble aggregates in both skeletal muscle and motor neurons; it also delays disease onset and progression, and increases survival. Our data suggest IGF-I as a potential treatment for SBMA and provide a specific mechanism for this beneficial effect. Moreover, our data highlights the skeletal muscle as alternative target for therapies SBMA, a disease that currently has no effective treatment