The protein misfolding and aggregation, typical of several neurodegenerative disease, are the results of an impairment of Protein Quality Control system (PQC). The PQC is composed by molecular chaperones, the Ubiquitin Proteasome System (UPS) and the autophagic pathway. Understanding the link between neurodegenerative diseases and the PQC might help to identify potential target for these diseases. To this purpose, we have studied the contribution of PQC in a motoneuron disease, the spinal and bulbar muscular atrophy (SBMA). SBMA is caused by a polyglutamine-expanded tract (polyQ) in the androgen receptor protein (AR). The binding of the ligand testosterone to the ARpolyQ induces protein misfolding and aggregation. The expanded polyQ tract confers a toxic gain-of-function to mutant AR that alters a cascade of several downstream pathways, including the PQC. Using SBMA motoneuronal cell line, we have already demonstrated that both the UPS and the autophagic pathway are altered or impaired. Thus, we studied the ability of different compounds of promoting ARpolyQ clearance through the potentiation of the PQC activity. We found that a combination of an autophagic inducer, trehalose, with an anti-androgen Bicalutamide, have synergic activity in the autophagic clearance of ARpolyQ., Also Berberine, a natural compound, was able to induce the ARpolyQ clearance possibly through the UPS. Moreover, using a SBMA knock-in mice model, we observed that in the spinal cord and in the skeletal muscle, the primary sites of pathogenesis, the UPS and the autophagic pathway seem to respond with a different degradative power to the ARpolyQ toxicity. These data suggest that the up-regulation of PQC may be beneficial for the treatment of SBMA, and these compounds might represent therapeutic candidates in SBMA and in other misfolding-related diseases. GRANTS: Fondazione AriSLA; Fondazione Cariplo; AFM Telethon France; Regione Lombardia; UNIMI; Telethon Italy.
|Titolo:||The protein quality control in spinal and bulbar muscular atrophy|
POLETTI, ANGELO (Ultimo)
|Data di pubblicazione:||18-set-2015|
|Settore Scientifico Disciplinare:||Settore BIO/13 - Biologia Applicata|
|Citazione:||The protein quality control in spinal and bulbar muscular atrophy / P. Rusmini, V. Crippa, R. Cristofani, M.E. Cicardi, A. Poletti. ((Intervento presentato al convegno The Biennal Congress of the Italian association of cell biology and differentiation tenutosi a Bologna nel 2015.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|