Spinal and Bulbar Muscular Atrophy (SBMA) is a 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 nuclei. 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.
Synergic prodegradative activity of bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy / E. Giorgetti, P. Rusmini, V. Crippa, R. Cristofani, A. Boncoraglio, M.E. Cicardi, M. Galbiati, A. Poletti. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 24:1(2015 Jan), pp. 64-75.
|Titolo:||Synergic prodegradative activity of bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy|
GIORGETTI, ELISA (Primo)
RUSMINI, PAOLA (Secondo)
GALBIATI, MARIARITA (Penultimo)
POLETTI, ANGELO (Corresponding)
|Parole Chiave:||transgenic mouse model; amyotrophic-lateral-sclerosis; elongated polyglutamine tract; protein B8 HSPB8; knock-in mice; motor-neurons; autophagic removal; 5-alpha-reductase type-2; aggregate formation; Kennedy-disease|
|Settore Scientifico Disciplinare:||Settore BIO/13 - Biologia Applicata|
Settore BIO/09 - Fisiologia
|Data di pubblicazione:||gen-2015|
|Data ahead of print / Data di stampa:||13-ago-2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1093/hmg/ddu419|
|Appare nelle tipologie:||01 - Articolo su periodico|