title: Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy.
abstract: 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.
authors.affiliation: Sezione di Biomedicina ed Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano 20133, Italy Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova e Roma Tor Vergata, Milano 20133, Italy Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA and.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giorgetti
authors.affiliation: Sezione di Biomedicina ed Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano 20133, Italy Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova e Roma Tor Vergata, Milano 20133, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.affiliation: Sezione di Biomedicina ed Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano 20133, Italy Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova e Roma Tor Vergata, Milano 20133, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.affiliation: Sezione di Biomedicina ed Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano 20133, Italy Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova e Roma Tor Vergata, Milano 20133, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cristofani
authors.affiliation: Sezione di Biomedicina ed Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano 20133, Italy Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova e Roma Tor Vergata, Milano 20133, Italy Department of Cell Biology, University Medical Center of Groningen, RB 9700 Groningen, The Netherlands.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Boncoraglio
authors.affiliation: Sezione di Biomedicina ed Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano 20133, Italy Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova e Roma Tor Vergata, Milano 20133, Italy.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Cicardi
authors.affiliation: Sezione di Biomedicina ed Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano 20133, Italy Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova e Roma Tor Vergata, Milano 20133, Italy.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Galbiati
authors.affiliation: Sezione di Biomedicina ed Endocrinologia, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano 20133, Italy Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova e Roma Tor Vergata, Milano 20133, Italy angelo.poletti@unimi.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004357:Drug Synergism; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D009570:Nitriles / Q000494:pharmacology*; D016716:PC12 Cells; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D014105:Tosyl Compounds / Q000494:pharmacology*; D014199:Trehalose / Q000494:pharmacology*
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; D014199:Trehalose