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.

Aberrant Autophagic Response in The Muscle of A Knock-in Mouse Model of Spinal and Bulbar Muscular Atrophy / P. Rusmini, M.J. Polanco, R. Cristofani, M.E. Cicardi, M. Meroni, M. Galbiati, M. Piccolella, E. Messi, E. Giorgetti, A.P. Lieberman, C. Milioto, A. Rocchi, T. Aggarwal, M. Pennuto, V. Crippa, A. Poletti. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 5:15174(2015 Oct 22), pp. 1-21. [10.1038/srep15174]

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

P. Rusmini
Primo
;
R. Cristofani;M.E. Cicardi;M. Meroni;M. Galbiati;M. Piccolella;E. Messi;E. Giorgetti;V. Crippa
Penultimo
;
A. Poletti
Ultimo
2015

Abstract

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.
Androgen receptor; motoneuron diseases; amyotrophic lateral sclerosis; kennedy's disease; Spinal and Bulbar Muscular Atrophy; SBMA; CAG repeat; polyglutamine; neurodegeneration; HSPB8; Protein quality control; autophagy; proteasome; BAG3; LC3; p62; muscle
Settore BIO/13 - Biologia Applicata
Settore BIO/09 - Fisiologia
22-ott-2015
Centro Interdipartimentale di Eccellenza per le Malattie Neurodegenerative CEND
Centro Interuniversitario di Ricerca sulle Basi Molecolari delle Malattie Neurodegenerative
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/329091
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