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 (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.
Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata and Milano, Italy.
Paola
P
Rusmini
Dulbecco Telethon Institute, Centre for Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy.
Maria Josefa
MJ
Polanco
Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata and Milano, Italy.
Riccardo
R
Cristofani
Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata and Milano, Italy.
Maria Elena
ME
Cicardi
Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata and Milano, Italy.
Marco
M
Meroni
Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata and Milano, Italy.
Mariarita
M
Galbiati
Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata and Milano, Italy.
Margherita
M
Piccolella
Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata and Milano, Italy.
Elio
E
Messi
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Elisa
E
Giorgetti
Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Andrew P
AP
Lieberman
Dulbecco Telethon Institute, Centre for Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy.|Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy.|Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova.
Carmelo
C
Milioto
Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy.
Anna
A
Rocchi
Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy.
Tanya
T
Aggarwal
Dulbecco Telethon Institute, Centre for Integrative Biology (CIBIO), Università degli Studi di Trento, Trento, Italy.
Maria
M
Pennuto
Laboratory of Experimental Neurobiology, C. Mondino National Neurological Institute, Pavia, Italy.
Valeria
V
Crippa
Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata and Milano, Italy.
Angelo
A
Poletti
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D055551:HSP27 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051379:Mice; D020966:Muscular Disorders, Atrophic / Q000235:genetics* / Q000473:pathology; D017510:Protein Folding; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
C410798:AR protein, human; D055551:HSP27 Heat-Shock Proteins; C442250:HSPB2 protein, human; D011944:Receptors, Androgen; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases