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.

17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy / P. Rusmini, F. Simonini, V. Crippa, E. Bolzoni, E. Onesto, M. Cagnin, D. Sau, N. Ferri, A. Poletti. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 41:1(2011 Jan), pp. 83-95.

17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy

P. Rusmini;F. Simonini;V. Crippa;E. Bolzoni;E. Onesto;D. Sau;N. Ferri;A. Poletti
2011-01

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.
SBMA ; Androgen receptor ; polyglutamine diseases ; CAG repeat ; motorneuron diseases ; neurodegeneration
Settore BIO/13 - Biologia Applicata
Settore BIO/14 - Farmacologia
NEUROBIOLOGY OF DISEASE
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/149207
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