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

Paola Rusmini, Francesca Simonini, Valeria Crippa, Elena Bolzoni, Elisa Onesto, Monica Cagnin, Daniela Sau, Nicola Ferri, Angelo Poletti

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)83-95
Number of pages13
JournalNeurobiology of Disease
Volume41
Issue number1
DOIs
Publication statusPublished - Jan 2011

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tanespimycin
Atrophic Muscular Disorders
Androgen Receptors
Mutant Proteins
Amyotrophic Lateral Sclerosis
Proteasome Endopeptidase Complex
Testosterone
Proteins
Pharmacology
Ligands

ASJC Scopus subject areas

  • Neurology

Cite this

Rusmini, P., Simonini, F., Crippa, V., Bolzoni, E., Onesto, E., Cagnin, M., ... Poletti, A. (2011). 17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy. Neurobiology of Disease, 41(1), 83-95. https://doi.org/10.1016/j.nbd.2010.08.023

17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy. / Rusmini, Paola; Simonini, Francesca; Crippa, Valeria; Bolzoni, Elena; Onesto, Elisa; Cagnin, Monica; Sau, Daniela; Ferri, Nicola; Poletti, Angelo.

In: Neurobiology of Disease, Vol. 41, No. 1, 01.2011, p. 83-95.

Research output: Contribution to journalArticle

Rusmini, P, Simonini, F, Crippa, V, Bolzoni, E, Onesto, E, Cagnin, M, Sau, D, Ferri, N & Poletti, A 2011, '17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy', Neurobiology of Disease, vol. 41, no. 1, pp. 83-95. https://doi.org/10.1016/j.nbd.2010.08.023
Rusmini, Paola ; Simonini, Francesca ; Crippa, Valeria ; Bolzoni, Elena ; Onesto, Elisa ; Cagnin, Monica ; Sau, Daniela ; Ferri, Nicola ; Poletti, Angelo. / 17-AAG increases autophagic removal of mutant androgen receptor in spinal and bulbar muscular atrophy. In: Neurobiology of Disease. 2011 ; Vol. 41, No. 1. pp. 83-95.
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