Pastore Nunzia, Annunziata Francesco, Colonna Rita, Maffia Veronica, Giuliano Teresa, Custode Bruno Maria, Lombardi Bernadette, Polishchuk Elena, Cacace Vincenzo, De Stefano Lucia, Nusco Edoardo, Sorrentino Nicolina Cristina, Piccolo Pasquale, Brunetti-Pierri Nicola
Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy; Department of Translational Medicine, Medical Genetics, University of Naples Federico II, Naples, Italy.
Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
Mol Ther. 2023 Sep 6;31(9):2651-2661. doi: 10.1016/j.ymthe.2023.06.018. Epub 2023 Jul 1.
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 Ca 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 reduces 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.
突变型Zα-1抗胰蛋白酶（ATZ）在肝脏中积聚成小球，是蛋白毒性肝病的典型代表。需要有针对清除聚合型ATZ的治疗策略。瞬时受体电位黏脂质1（TRPML1）是一种溶酶体钙通道，可维持溶酶体的稳态。在本研究中，我们表明，通过增加溶酶体胞吐作用，TRPML1基因转移或小分子介导的TRPML1激活可减少表达人ATZ的PiZ转基因小鼠肝脏中的ATZ小球和纤维化。TRPML1诱导的ATZ小球清除过程中，自噬或转录因子EB（TFEB）的核转位并未增加。我们的结果表明，靶向TRPML1和溶酶体胞吐作用是治疗由ATZ引起的肝病以及可能由蛋白毒性肝脏蓄积引起的其他疾病的一种新方法。
