Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy
| العنوان: | Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy |
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| المؤلفون: | Paola Rusmini, Angelo Poletti, Valeria Crippa, Maria Elena Cicardi, Elisa Giorgetti, Riccardo Cristofani, Mariarita Galbiati, A. Boncoraglio |
| المصدر: | Human Molecular Genetics, 24(1), 64-75. Oxford University Press Human Molecular Genetics |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | PC12 Cells, AMYOTROPHIC-LATERAL-SCLEROSIS, Tosyl Compounds, chemistry.chemical_compound, AUTOPHAGIC REMOVAL, Anilides, PROTEIN B8 HSPB8, KENNEDY-DISEASE, Genetics (clinical), Motor Neurons, ELONGATED POLYGLUTAMINE TRACT, Drug Synergism, Articles, General Medicine, Protein Transport, medicine.anatomical_structure, Receptors, Androgen, Dihydrotestosterone, medicine.drug, medicine.medical_specialty, KNOCK-IN MICE, Bicalutamide, 5-ALPHA-REDUCTASE TYPE-2, Bulbo-Spinal Atrophy, X-Linked, Biology, Cell Line, Gene knockin, Internal medicine, Nitriles, Autophagy, Genetics, medicine, Animals, Humans, TRANSGENIC MOUSE MODEL, Molecular Biology, Trehalose, Androgen Antagonists, medicine.disease, Rats, AGGREGATE FORMATION, Androgen receptor, Cell nucleus, Spinal and bulbar muscular atrophy, Endocrinology, chemistry, Mutation, MOTOR-NEURONS |
| الوصف: | 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 (R)), 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. |
| اللغة: | English |
| تدمد: | 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::538117ea167b3186f6106ac4f1d4103fTest https://doi.org/10.1093/hmg/ddu419Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....538117ea167b3186f6106ac4f1d4103f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 09646906 |
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