title: 17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy.
abstract: Several types of motorneuron diseases are linked to neurotoxic mutant proteins. These acquire aberrant conformations (misfolding) that trigger deleterious downstream events responsible for neuronal dysfunction and degeneration. The pharmacological removal of misfolded proteins might thus be useful in these diseases. We utilized a peculiar motorneuronal disease model, spinobulbar muscular atrophy (SBMA), in which the neurotoxicity of the protein involved, the mutant androgen receptor (ARpolyQ), can be modulated by its ligand testosterone (T). 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) has already been proven to exert beneficial action in SBMA. Here we demonstrated that 17-AAG exerts its pro-degradative activity on mutant ARpolyQ without impacting on proteasome functions. 17-AAG removes ARpolyQ misfolded species and aggregates by activating the autophagic system. We next analyzed the 17-AAG effects on two proteins (SOD1 and TDP-43) involved in related motorneuronal diseases, such as amyotrophic lateral sclerosis (ALS). In these models 17-AAG was unable to counteract protein aggregation.
authors.affiliation: Dipartimento di Endocrinologia, Fisiopatologia e Biologia Applicata, and Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.forename: Francesca
authors.initials: F
authors.lastname: Simonini
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.forename: Elena
authors.initials: E
authors.lastname: Bolzoni
authors.forename: Elisa
authors.initials: E
authors.lastname: Onesto
authors.forename: Monica
authors.initials: M
authors.lastname: Cagnin
authors.forename: Daniela
authors.initials: D
authors.lastname: Sau
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferri
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D016227:Benzoquinones / Q000494:pharmacology* / Q000627:therapeutic use; D002461:Cell Line, Transformed; D047029:Lactams, Macrocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology; D057165:Proteostasis Deficiencies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D018696:Neuroprotective Agents; D011944:Receptors, Androgen; C112765:tanespimycin