| First Author | Soria LR | Year | 2021 |
| Journal | EMBO Mol Med | Volume | 13 |
| Issue | 2 | Pages | e13158 |
| PubMed ID | 33369168 | Mgi Jnum | J:336944 |
| Mgi Id | MGI:6804627 | Doi | 10.15252/emmm.202013158 |
| Citation | Soria LR, et al. (2021) Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders. EMBO Mol Med 13(2):e13158 |
| abstractText | 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. |
