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Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy

Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (...

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Autores principales: Rusmini, Paola, Polanco, Maria Josefa, Cristofani, Riccardo, Cicardi, Maria Elena, Meroni, Marco, Galbiati, Mariarita, Piccolella, Margherita, Messi, Elio, Giorgetti, Elisa, Lieberman, Andrew P., Milioto, Carmelo, Rocchi, Anna, Aggarwal, Tanya, Pennuto, Maria, Crippa, Valeria, Poletti, Angelo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614888/
https://www.ncbi.nlm.nih.gov/pubmed/26490709
http://dx.doi.org/10.1038/srep15174
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author Rusmini, Paola
Polanco, Maria Josefa
Cristofani, Riccardo
Cicardi, Maria Elena
Meroni, Marco
Galbiati, Mariarita
Piccolella, Margherita
Messi, Elio
Giorgetti, Elisa
Lieberman, Andrew P.
Milioto, Carmelo
Rocchi, Anna
Aggarwal, Tanya
Pennuto, Maria
Crippa, Valeria
Poletti, Angelo
author_facet Rusmini, Paola
Polanco, Maria Josefa
Cristofani, Riccardo
Cicardi, Maria Elena
Meroni, Marco
Galbiati, Mariarita
Piccolella, Margherita
Messi, Elio
Giorgetti, Elisa
Lieberman, Andrew P.
Milioto, Carmelo
Rocchi, Anna
Aggarwal, Tanya
Pennuto, Maria
Crippa, Valeria
Poletti, Angelo
author_sort Rusmini, Paola
collection PubMed
description Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGFβ1 and PGC-1α were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3:BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments.
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spelling pubmed-46148882015-10-29 Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy Rusmini, Paola Polanco, Maria Josefa Cristofani, Riccardo Cicardi, Maria Elena Meroni, Marco Galbiati, Mariarita Piccolella, Margherita Messi, Elio Giorgetti, Elisa Lieberman, Andrew P. Milioto, Carmelo Rocchi, Anna Aggarwal, Tanya Pennuto, Maria Crippa, Valeria Poletti, Angelo Sci Rep Article Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGFβ1 and PGC-1α were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3:BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments. Nature Publishing Group 2015-10-22 /pmc/articles/PMC4614888/ /pubmed/26490709 http://dx.doi.org/10.1038/srep15174 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Rusmini, Paola
Polanco, Maria Josefa
Cristofani, Riccardo
Cicardi, Maria Elena
Meroni, Marco
Galbiati, Mariarita
Piccolella, Margherita
Messi, Elio
Giorgetti, Elisa
Lieberman, Andrew P.
Milioto, Carmelo
Rocchi, Anna
Aggarwal, Tanya
Pennuto, Maria
Crippa, Valeria
Poletti, Angelo
Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy
title Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy
title_full Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy
title_fullStr Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy
title_full_unstemmed Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy
title_short Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy
title_sort aberrant autophagic response in the muscle of a knock-in mouse model of spinal and bulbar muscular atrophy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614888/
https://www.ncbi.nlm.nih.gov/pubmed/26490709
http://dx.doi.org/10.1038/srep15174
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