TY - JOUR T1 - Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders JF - bioRxiv DO - 10.1101/2020.07.22.216382 SP - 2020.07.22.216382 AU - Leandro R. Soria AU - Dany P. Perocheau AU - Giulia De Sabbata AU - Angela De Angelis AU - Gemma Bruno AU - Elena Polishchuk AU - Sonam Gurung AU - Debora Paris AU - Paola Cuomo AU - Andrea Motta AU - Michael Orford AU - Simon Eaton AU - Simon Waddington AU - Carmine Settembre AU - Andrés F. Muro AU - Julien Baruteau AU - Nicola Brunetti-Pierri Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/24/2020.07.22.216382.abstract N2 - Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unraveled Beclin-1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell penetrating autophagy inducing Tat-Beclin-1 (TB-1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB-1 reduced urinary orotic acid and hyperammonemia, and improved survival under protein-rich diet in spf-ash mice, a model of OTC deficiency (proximal UCD). In AslNeo/Neo mice, a model of ASL deficiency (distal UCD), TB-1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in AslNeo/Neo mice. In conclusion, Beclin-1-dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle. ER -