Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease due to a CAG triplet-repeat expansion in the
androgen receptor (AR) gene, which is translated into an elongated
polyglutamine (
polyQ) tract in AR
protein (ARpolyQ). ARpolyQ toxicity is activated by the AR
ligand testosterone (or
dihydrotestosterone), and the
polyQ triggers ARpolyQ misfolding and aggregation in spinal cord motoneurons and muscle cells. In motoneurons,
testosterone triggers nuclear toxicity by inducing AR nuclear translocation. Thus, (i) prevention of ARpolyQ nuclear localization, combined with (ii) an increased ARpolyQ cytoplasmic clearance, should reduce its detrimental activity. Using the
antiandrogen Bicalutamide (
Casodex(®)), which slows down AR activation and nuclear translocation, and the
disaccharide trehalose, an autophagy activator, we found that, in motoneurons, the two compounds together reduced ARpolyQ insoluble forms with higher efficiency than that obtained with single treatments. The ARpolyQ clearance was mediated by
trehalose-induced autophagy combined with the longer cytoplasmic retention of ARpolyQ bound to
Bicalutamide. This allows an increased recognition of misfolded species by the autophagic system prior to their migration into the nucleus. Interestingly, the combinatory use of
trehalose and
Bicalutamide was also efficient in the removal of insoluble species of AR with a very long
polyQ (Q112) tract, which typically aggregates into the cell nuclei. Collectively, these data suggest that the combinatory use of
Bicalutamide and
trehalose is a novel approach to facilitate ARpolyQ clearance that has to be tested in other cell types target of SBMA (i.e. muscle cells) and in vivo in animal models of SBMA.