title: The Role of the Protein Quality Control System in SBMA.
abstract: Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked disease associated with the expansion of the CAG triplet repeat present in exon 1 of the androgen receptor (AR) gene. This results in the production of a mutant AR containing an elongated polyglutamine tract (polyQ) in its N-terminus. Interestingly, the ARpolyQ becomes toxic only after its activation by the natural androgenic ligands, possibly because of aberrant androgen-induced conformational changes of the ARpolyQ, which generate misfolded species. These misfolded ARpolyQ species must be cleared from motoneurons and muscle cells, and this process is mediated by the protein quality control (PQC) system. Experimental evidence suggested that failure of the PQC pathways occurs in disease, leading to ARpolyQ accumulation and toxicity in the target cells. In this review, we summarized the overall impact of mutant and misfolded ARpolyQ on the PQC system and described how molecular chaperones and the degradative pathways (ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), and the unfolded protein response (UPR), which activates the endoplasmic reticulum-associated degradation (ERAD)) are differentially affected in SBMA. We also extensively and critically reviewed several molecular and pharmacological approaches proposed to restore a global intracellular activity of the PQC system. Collectively, these data suggest that the fine and delicate equilibrium existing among the different players of the PQC system could be restored in a therapeutic perspective by the synergic/additive activities of compounds designed to tackle sequential or alternative steps of the intracellular defense mechanisms triggered against proteotoxic misfolded species.
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rusmini
authors.affiliation: Laboratory of Experimental Neurobiology, C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata, Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Cristofani
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Rinaldi
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata, Milan, Italy.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Cicardi
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata, Milan, Italy.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Galbiati
authors.affiliation: Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze, Università di Modena e Reggio Emilia, Modena, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Carra
authors.affiliation: The Graham Watts Laboratories for Research into Motor Neuron Disease, Sobell Department of Motor Neuroscience, MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London, UK.
authors.forename: Bilal
authors.initials: B
authors.lastname: Malik
authors.affiliation: The Graham Watts Laboratories for Research into Motor Neuron Disease, Sobell Department of Motor Neuroscience, MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. angelo.poletti@unimi.it.|Centro InterUniversitario sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Genova, Roma Tor Vergata, Milan, Italy. angelo.poletti@unimi.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
mesh_terms: D000818:Animals; D055534:Bulbo-Spinal Atrophy, X-Linked / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000737:chemistry; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion; D056811:Unfolded Protein Response
chemical_list: D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine
keywords: Aggregation; Androgen receptor; Autophagy; BAG3; CAG triplet repeat; Chaperones; ERAD; HSPB8; Misfolded protein; Motoneuron diseases; Muscle; Neurodegeneration; Polyglutamine; Proteasome; Protein quality control system; Proteotoxicity; Rusmini Paola, Crippa Valeria, Greensmith Linda, and Poletti Angelo equally contributed to this study.; SBMA; Testosterone; UPR