Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders
Abstract 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 hyper...
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| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-12-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202013158 |
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| author | Leandro R Soria Sonam Gurung Giulia De Sabbata Dany P Perocheau Angela De Angelis Gemma Bruno Elena Polishchuk Debora Paris Paola Cuomo Andrea Motta Michael Orford Youssef Khalil Simon Eaton Philippa B Mills Simon N Waddington Carmine Settembre Andrés F Muro Julien Baruteau Nicola Brunetti‐Pierri |
| author_facet | Leandro R Soria Sonam Gurung Giulia De Sabbata Dany P Perocheau Angela De Angelis Gemma Bruno Elena Polishchuk Debora Paris Paola Cuomo Andrea Motta Michael Orford Youssef Khalil Simon Eaton Philippa B Mills Simon N Waddington Carmine Settembre Andrés F Muro Julien Baruteau Nicola Brunetti‐Pierri |
| author_sort | Leandro R Soria |
| collection | DOAJ |
| description | Abstract 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 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. |
| format | Article |
| id | doaj-art-19085dda865a4f648e70bb866bfbf0bc |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-19085dda865a4f648e70bb866bfbf0bc2025-08-20T03:46:11ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-12-0113211410.15252/emmm.202013158Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disordersLeandro R Soria0Sonam Gurung1Giulia De Sabbata2Dany P Perocheau3Angela De Angelis4Gemma Bruno5Elena Polishchuk6Debora Paris7Paola Cuomo8Andrea Motta9Michael Orford10Youssef Khalil11Simon Eaton12Philippa B Mills13Simon N Waddington14Carmine Settembre15Andrés F Muro16Julien Baruteau17Nicola Brunetti‐Pierri18Telethon Institute of Genetics and MedicineUCL Great Ormond Street Institute of Child HealthInternational Centre for Genetic Engineering and BiotechnologyUCL Great Ormond Street Institute of Child HealthTelethon Institute of Genetics and MedicineTelethon Institute of Genetics and MedicineTelethon Institute of Genetics and MedicineInstitute of Biomolecular Chemistry, National Research CouncilInstitute of Biomolecular Chemistry, National Research CouncilInstitute of Biomolecular Chemistry, National Research CouncilUCL Great Ormond Street Institute of Child HealthUCL Great Ormond Street Institute of Child HealthUCL Great Ormond Street Institute of Child HealthUCL Great Ormond Street Institute of Child HealthUCL Great Ormond Street Institute of Child HealthTelethon Institute of Genetics and MedicineInternational Centre for Genetic Engineering and BiotechnologyUCL Great Ormond Street Institute of Child HealthTelethon Institute of Genetics and MedicineAbstract 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 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.https://doi.org/10.15252/emmm.202013158argininosuccinic aciduriaautophagyOTC deficiencyTat‐Beclin‐1 peptideurea cycle disorders |
| spellingShingle | Leandro R Soria Sonam Gurung Giulia De Sabbata Dany P Perocheau Angela De Angelis Gemma Bruno Elena Polishchuk Debora Paris Paola Cuomo Andrea Motta Michael Orford Youssef Khalil Simon Eaton Philippa B Mills Simon N Waddington Carmine Settembre Andrés F Muro Julien Baruteau Nicola Brunetti‐Pierri Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders EMBO Molecular Medicine argininosuccinic aciduria autophagy OTC deficiency Tat‐Beclin‐1 peptide urea cycle disorders |
| title | Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
| title_full | Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
| title_fullStr | Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
| title_full_unstemmed | Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
| title_short | Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
| title_sort | beclin 1 mediated activation of autophagy improves proximal and distal urea cycle disorders |
| topic | argininosuccinic aciduria autophagy OTC deficiency Tat‐Beclin‐1 peptide urea cycle disorders |
| url | https://doi.org/10.15252/emmm.202013158 |
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