Increased expression or activation of TRPML1 reduces hepatic storage of toxic Z alpha-1 antitrypsin

Authors: Nunzia Pastore, Francesco Annunziata, Rita Colonna, Veronica Maffia, Teresa Giuliano, Bruno Maria Custode, Bernadette Lombardi, Elena Polishchuk, Vincenzo Cacace, Lucia De Stefano, Edoardo Nusco, Nicolina Cristina Sorrentino, Pasquale Piccolo, Nicola Brunetti-Pierri
Year: 2023
Sources: Molecular Therapy

Mutant Z-alpha-1 antitrypsin (ATZ) accumulates in globules in the liver and is the prototype of proteotoxic hepatic disease. Therapeutic strategies aiming at clearance of polymeric ATZ are needed. Transient receptor potential mucolipin 1 (TRPML1) is a lysosomal Ca2+ channel that maintains lysosomal homeostasis. In this study, we show that by increasing lysosomal exocytosis, TRPML1 gene transfer or small molecule-mediated activation of TRPML1 reduce hepatic ATZ globules and fibrosis in PiZ transgenic mice that express the human ATZ. ATZ globule clearance induced by TRPML1 occurred without increase in autophagy or nuclear translocation of TFEB. Our results show that targeting TRPML1 and lysosomal exocytosis is a novel approach for treatment of the liver disease due to ATZ and potentially other diseases due to proteotoxic liver storage.

Category: journals