Open AccessBeclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders
Author(s) -
Soria Leandro R,
Gurung Sonam,
De Sabbata Giulia,
Perocheau Dany P,
De Angelis Angela,
Bruno Gemma,
Polishchuk Elena,
Paris Debora,
Cuomo Paola,
Motta Andrea,
Orford Michael,
Khalil Youssef,
Eaton Simon,
Mills Philippa B,
Waddington Simon N,
Settembre Carmine,
Muro Andrés F,
Baruteau Julien,
BrunettiPierri Nicola
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202013158
Subject(s) - library science , computer science
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 unravelled 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 improved survival under protein‐rich diet in spf‐ash mice, a model of OTC deficiency (proximal UCD). In Asl Neo/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 Asl Neo/Neo mice. In conclusion, Beclin‐1‐dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle.