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 mo- toneurons 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 de- scribed how molecular chaperones and the degradative path- ways (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 intra- cellular 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.
The Role of the Protein Quality Control System in SBMA / P. Rusmini, V. Crippa, R. Cristofani, C. Rinaldi, M.E. Cicardi, M. Galbiati, S. Carra, M. Bilal, L. Greensmith, A. Poletti. - In: JOURNAL OF MOLECULAR NEUROSCIENCE. - ISSN 0895-8696. - 58:3(2016 Mar), pp. 348-364.
|Titolo:||The Role of the Protein Quality Control System in SBMA|
RUSMINI, PAOLA (Primo)
CRIPPA, VALERIA (Secondo)
POLETTI, ANGELO (Ultimo)
|Parole Chiave:||androgen receptor; spinal and bulbar muscular atrophy; motor neuron diseases; neurodegeneration; protein misfolding; protein aggregation; protein quality control system; hspB8; HSP70; chaperones; autophagy; proteasome; neurotoxicity; BAG3; BAG1; UPS; UPR; ERAD; endoplasmic reticulum; testosterone; polyglutamine; CAG triplet repeat; muscle; SBMA; proteotoxicity; HSPB8|
|Settore Scientifico Disciplinare:||Settore BIO/13 - Biologia Applicata|
Settore BIO/09 - Fisiologia
|Data di pubblicazione:||mar-2016|
|Centro di ricerca:||Centro Interdipartimentale di Eccellenza per le Malattie Neurodegenerative CEND|
Centro Interuniversitario di Ricerca sulle Basi Molecolari delle Malattie Neurodegenerative
|Data ahead of print / Data di stampa:||14-nov-2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1007/s12031-015-0675-6|
|Appare nelle tipologie:||01 - Articolo su periodico|