17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy.
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.
Rusmini
Paola
P
Dipartimento di Endocrinologia, Fisiopatologia e Biologia Applicata, and Centre of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Italy.
Simonini
Francesca
F
Crippa
Valeria
V
Bolzoni
Elena
E
Onesto
Elisa
E
Cagnin
Monica
M
Sau
Daniela
D
Ferri
Nicola
N
Poletti
Angelo
A
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
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D018696:Neuroprotective Agents; D011944:Receptors, Androgen; C112765:tanespimycin