The Role of the Protein Quality Control System in SBMA
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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.
KeywordsAndrogen receptor Polyglutamine CAG triplet repeat Neurodegeneration Motoneuron diseases Muscle SBMA Testosterone Autophagy Protein quality control system Proteotoxicity Proteasome UPR ERAD HSPB8 Chaperones Misfolded protein Aggregation BAG3 Rusmini Paola, Crippa Valeria, Greensmith Linda, and Poletti Angelo equally contributed to this study.
The following grants are gratefully acknowledged: Fondazione Telethon, Italy (n. GGP14039); Fondazione Cariplo, Italy (n. 2014–0686); Fondazione AriSLA, Italy (n. ALS_HSPB8 and ALS_Granulopathy); Association Française contre les Myopathies (AFM Telethon), France (n. 16,406); Regione Lombardia; Università degli Studi di Milano e piano di sviluppo UNIMI - linea B; and Italian Ministry of Health (n. GR-2011-02347198); EU Joint Programme - Neurodegenerative Disease Research (JPND).
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