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...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Soria, Leandro R [verfasserIn] Gurung, Sonam [verfasserIn] De Sabbata, Giulia [verfasserIn] Perocheau, Dany P [verfasserIn] De Angelis, Angela [verfasserIn] Bruno, Gemma [verfasserIn] Polishchuk, Elena [verfasserIn] Paris, Debora [verfasserIn] Cuomo, Paola [verfasserIn] Motta, Andrea [verfasserIn] Orford, Michael [verfasserIn] Khalil, Youssef [verfasserIn] Eaton, Simon [verfasserIn] Mills, Philippa B [verfasserIn] Waddington, Simon N [verfasserIn] Settembre, Carmine [verfasserIn] Muro, Andrés F [verfasserIn] Baruteau, Julien [verfasserIn] Brunetti‐Pierri, Nicola [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2020 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2020 |
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| Übergeordnetes Werk: |
Enthalten in: EMBO Molecular Medicine - Nature Publishing Group UK, 2023, 13(2020), 2 vom: 28. Dez. |
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| Übergeordnetes Werk: |
volume:13 ; year:2020 ; number:2 ; day:28 ; month:12 |
| Links: |
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| DOI / URN: |
10.15252/emmm.202013158 |
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| Katalog-ID: |
SPR058031332 |
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| 100 | 1 | |a Soria, Leandro R |e verfasserin |0 (orcid)0000-0002-7124-856X |4 aut | |
| 245 | 1 | 0 | |a Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
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| 520 | |a 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. | ||
| 520 | |a Synopsis Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. Beclin‐1 is a central player in autophagy and a knock‐in mouse model carrying a Becn1 mutation resulting in constitutively active autophagy shows enhanced ureagenesis and increased ammonia detoxification.TB‐1 improves biochemical abnormalities and increases survival of mice with OTC deficiency (proximal urea cycle disorder).TB‐1 improves biochemical abnormalities and survival of mice with ASL deficiency (distal urea cycle disorder).ASL deficient mice show cytoplasmic and nuclear glycogen accumulation that are both reduced by TB‐1. | ||
| 520 | |a Graphical Abstract Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. | ||
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| 650 | 4 | |a urea cycle disorders |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Gurung, Sonam |e verfasserin |4 aut | |
| 700 | 1 | |a De Sabbata, Giulia |e verfasserin |4 aut | |
| 700 | 1 | |a Perocheau, Dany P |e verfasserin |0 (orcid)0000-0001-5450-8801 |4 aut | |
| 700 | 1 | |a De Angelis, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Bruno, Gemma |e verfasserin |4 aut | |
| 700 | 1 | |a Polishchuk, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Paris, Debora |e verfasserin |4 aut | |
| 700 | 1 | |a Cuomo, Paola |e verfasserin |4 aut | |
| 700 | 1 | |a Motta, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Orford, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Khalil, Youssef |e verfasserin |0 (orcid)0000-0001-9025-3017 |4 aut | |
| 700 | 1 | |a Eaton, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Mills, Philippa B |e verfasserin |4 aut | |
| 700 | 1 | |a Waddington, Simon N |e verfasserin |4 aut | |
| 700 | 1 | |a Settembre, Carmine |e verfasserin |0 (orcid)0000-0002-5829-8589 |4 aut | |
| 700 | 1 | |a Muro, Andrés F |e verfasserin |0 (orcid)0000-0002-9628-0494 |4 aut | |
| 700 | 1 | |a Baruteau, Julien |e verfasserin |0 (orcid)0000-0003-0582-540X |4 aut | |
| 700 | 1 | |a Brunetti‐Pierri, Nicola |e verfasserin |0 (orcid)0000-0002-6895-8819 |4 aut | |
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10.15252/emmm.202013158 doi (DE-627)SPR058031332 (SPR)emmm.202013158-e DE-627 ger DE-627 rakwb eng Soria, Leandro R verfasserin (orcid)0000-0002-7124-856X aut Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 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. Synopsis Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. Beclin‐1 is a central player in autophagy and a knock‐in mouse model carrying a Becn1 mutation resulting in constitutively active autophagy shows enhanced ureagenesis and increased ammonia detoxification.TB‐1 improves biochemical abnormalities and increases survival of mice with OTC deficiency (proximal urea cycle disorder).TB‐1 improves biochemical abnormalities and survival of mice with ASL deficiency (distal urea cycle disorder).ASL deficient mice show cytoplasmic and nuclear glycogen accumulation that are both reduced by TB‐1. Graphical Abstract Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. argininosuccinic aciduria (dpeaa)DE-He213 autophagy (dpeaa)DE-He213 OTC deficiency (dpeaa)DE-He213 Tat‐Beclin‐1 peptide (dpeaa)DE-He213 urea cycle disorders (dpeaa)DE-He213 Gurung, Sonam verfasserin aut De Sabbata, Giulia verfasserin aut Perocheau, Dany P verfasserin (orcid)0000-0001-5450-8801 aut De Angelis, Angela verfasserin aut Bruno, Gemma verfasserin aut Polishchuk, Elena verfasserin aut Paris, Debora verfasserin aut Cuomo, Paola verfasserin aut Motta, Andrea verfasserin aut Orford, Michael verfasserin aut Khalil, Youssef verfasserin (orcid)0000-0001-9025-3017 aut Eaton, Simon verfasserin aut Mills, Philippa B verfasserin aut Waddington, Simon N verfasserin aut Settembre, Carmine verfasserin (orcid)0000-0002-5829-8589 aut Muro, Andrés F verfasserin (orcid)0000-0002-9628-0494 aut Baruteau, Julien verfasserin (orcid)0000-0003-0582-540X aut Brunetti‐Pierri, Nicola verfasserin (orcid)0000-0002-6895-8819 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 13(2020), 2 vom: 28. Dez. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:13 year:2020 number:2 day:28 month:12 https://dx.doi.org/10.15252/emmm.202013158 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2020 2 28 12 |
| spelling |
10.15252/emmm.202013158 doi (DE-627)SPR058031332 (SPR)emmm.202013158-e DE-627 ger DE-627 rakwb eng Soria, Leandro R verfasserin (orcid)0000-0002-7124-856X aut Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 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. Synopsis Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. Beclin‐1 is a central player in autophagy and a knock‐in mouse model carrying a Becn1 mutation resulting in constitutively active autophagy shows enhanced ureagenesis and increased ammonia detoxification.TB‐1 improves biochemical abnormalities and increases survival of mice with OTC deficiency (proximal urea cycle disorder).TB‐1 improves biochemical abnormalities and survival of mice with ASL deficiency (distal urea cycle disorder).ASL deficient mice show cytoplasmic and nuclear glycogen accumulation that are both reduced by TB‐1. Graphical Abstract Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. argininosuccinic aciduria (dpeaa)DE-He213 autophagy (dpeaa)DE-He213 OTC deficiency (dpeaa)DE-He213 Tat‐Beclin‐1 peptide (dpeaa)DE-He213 urea cycle disorders (dpeaa)DE-He213 Gurung, Sonam verfasserin aut De Sabbata, Giulia verfasserin aut Perocheau, Dany P verfasserin (orcid)0000-0001-5450-8801 aut De Angelis, Angela verfasserin aut Bruno, Gemma verfasserin aut Polishchuk, Elena verfasserin aut Paris, Debora verfasserin aut Cuomo, Paola verfasserin aut Motta, Andrea verfasserin aut Orford, Michael verfasserin aut Khalil, Youssef verfasserin (orcid)0000-0001-9025-3017 aut Eaton, Simon verfasserin aut Mills, Philippa B verfasserin aut Waddington, Simon N verfasserin aut Settembre, Carmine verfasserin (orcid)0000-0002-5829-8589 aut Muro, Andrés F verfasserin (orcid)0000-0002-9628-0494 aut Baruteau, Julien verfasserin (orcid)0000-0003-0582-540X aut Brunetti‐Pierri, Nicola verfasserin (orcid)0000-0002-6895-8819 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 13(2020), 2 vom: 28. Dez. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:13 year:2020 number:2 day:28 month:12 https://dx.doi.org/10.15252/emmm.202013158 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2020 2 28 12 |
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10.15252/emmm.202013158 doi (DE-627)SPR058031332 (SPR)emmm.202013158-e DE-627 ger DE-627 rakwb eng Soria, Leandro R verfasserin (orcid)0000-0002-7124-856X aut Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 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. Synopsis Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. Beclin‐1 is a central player in autophagy and a knock‐in mouse model carrying a Becn1 mutation resulting in constitutively active autophagy shows enhanced ureagenesis and increased ammonia detoxification.TB‐1 improves biochemical abnormalities and increases survival of mice with OTC deficiency (proximal urea cycle disorder).TB‐1 improves biochemical abnormalities and survival of mice with ASL deficiency (distal urea cycle disorder).ASL deficient mice show cytoplasmic and nuclear glycogen accumulation that are both reduced by TB‐1. Graphical Abstract Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. argininosuccinic aciduria (dpeaa)DE-He213 autophagy (dpeaa)DE-He213 OTC deficiency (dpeaa)DE-He213 Tat‐Beclin‐1 peptide (dpeaa)DE-He213 urea cycle disorders (dpeaa)DE-He213 Gurung, Sonam verfasserin aut De Sabbata, Giulia verfasserin aut Perocheau, Dany P verfasserin (orcid)0000-0001-5450-8801 aut De Angelis, Angela verfasserin aut Bruno, Gemma verfasserin aut Polishchuk, Elena verfasserin aut Paris, Debora verfasserin aut Cuomo, Paola verfasserin aut Motta, Andrea verfasserin aut Orford, Michael verfasserin aut Khalil, Youssef verfasserin (orcid)0000-0001-9025-3017 aut Eaton, Simon verfasserin aut Mills, Philippa B verfasserin aut Waddington, Simon N verfasserin aut Settembre, Carmine verfasserin (orcid)0000-0002-5829-8589 aut Muro, Andrés F verfasserin (orcid)0000-0002-9628-0494 aut Baruteau, Julien verfasserin (orcid)0000-0003-0582-540X aut Brunetti‐Pierri, Nicola verfasserin (orcid)0000-0002-6895-8819 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 13(2020), 2 vom: 28. Dez. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:13 year:2020 number:2 day:28 month:12 https://dx.doi.org/10.15252/emmm.202013158 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2020 2 28 12 |
| allfieldsGer |
10.15252/emmm.202013158 doi (DE-627)SPR058031332 (SPR)emmm.202013158-e DE-627 ger DE-627 rakwb eng Soria, Leandro R verfasserin (orcid)0000-0002-7124-856X aut Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 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. Synopsis Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. Beclin‐1 is a central player in autophagy and a knock‐in mouse model carrying a Becn1 mutation resulting in constitutively active autophagy shows enhanced ureagenesis and increased ammonia detoxification.TB‐1 improves biochemical abnormalities and increases survival of mice with OTC deficiency (proximal urea cycle disorder).TB‐1 improves biochemical abnormalities and survival of mice with ASL deficiency (distal urea cycle disorder).ASL deficient mice show cytoplasmic and nuclear glycogen accumulation that are both reduced by TB‐1. Graphical Abstract Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. argininosuccinic aciduria (dpeaa)DE-He213 autophagy (dpeaa)DE-He213 OTC deficiency (dpeaa)DE-He213 Tat‐Beclin‐1 peptide (dpeaa)DE-He213 urea cycle disorders (dpeaa)DE-He213 Gurung, Sonam verfasserin aut De Sabbata, Giulia verfasserin aut Perocheau, Dany P verfasserin (orcid)0000-0001-5450-8801 aut De Angelis, Angela verfasserin aut Bruno, Gemma verfasserin aut Polishchuk, Elena verfasserin aut Paris, Debora verfasserin aut Cuomo, Paola verfasserin aut Motta, Andrea verfasserin aut Orford, Michael verfasserin aut Khalil, Youssef verfasserin (orcid)0000-0001-9025-3017 aut Eaton, Simon verfasserin aut Mills, Philippa B verfasserin aut Waddington, Simon N verfasserin aut Settembre, Carmine verfasserin (orcid)0000-0002-5829-8589 aut Muro, Andrés F verfasserin (orcid)0000-0002-9628-0494 aut Baruteau, Julien verfasserin (orcid)0000-0003-0582-540X aut Brunetti‐Pierri, Nicola verfasserin (orcid)0000-0002-6895-8819 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 13(2020), 2 vom: 28. Dez. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:13 year:2020 number:2 day:28 month:12 https://dx.doi.org/10.15252/emmm.202013158 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2020 2 28 12 |
| allfieldsSound |
10.15252/emmm.202013158 doi (DE-627)SPR058031332 (SPR)emmm.202013158-e DE-627 ger DE-627 rakwb eng Soria, Leandro R verfasserin (orcid)0000-0002-7124-856X aut Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 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. Synopsis Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. Beclin‐1 is a central player in autophagy and a knock‐in mouse model carrying a Becn1 mutation resulting in constitutively active autophagy shows enhanced ureagenesis and increased ammonia detoxification.TB‐1 improves biochemical abnormalities and increases survival of mice with OTC deficiency (proximal urea cycle disorder).TB‐1 improves biochemical abnormalities and survival of mice with ASL deficiency (distal urea cycle disorder).ASL deficient mice show cytoplasmic and nuclear glycogen accumulation that are both reduced by TB‐1. Graphical Abstract Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. argininosuccinic aciduria (dpeaa)DE-He213 autophagy (dpeaa)DE-He213 OTC deficiency (dpeaa)DE-He213 Tat‐Beclin‐1 peptide (dpeaa)DE-He213 urea cycle disorders (dpeaa)DE-He213 Gurung, Sonam verfasserin aut De Sabbata, Giulia verfasserin aut Perocheau, Dany P verfasserin (orcid)0000-0001-5450-8801 aut De Angelis, Angela verfasserin aut Bruno, Gemma verfasserin aut Polishchuk, Elena verfasserin aut Paris, Debora verfasserin aut Cuomo, Paola verfasserin aut Motta, Andrea verfasserin aut Orford, Michael verfasserin aut Khalil, Youssef verfasserin (orcid)0000-0001-9025-3017 aut Eaton, Simon verfasserin aut Mills, Philippa B verfasserin aut Waddington, Simon N verfasserin aut Settembre, Carmine verfasserin (orcid)0000-0002-5829-8589 aut Muro, Andrés F verfasserin (orcid)0000-0002-9628-0494 aut Baruteau, Julien verfasserin (orcid)0000-0003-0582-540X aut Brunetti‐Pierri, Nicola verfasserin (orcid)0000-0002-6895-8819 aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 13(2020), 2 vom: 28. Dez. (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:13 year:2020 number:2 day:28 month:12 https://dx.doi.org/10.15252/emmm.202013158 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2020 2 28 12 |
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English |
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Enthalten in EMBO Molecular Medicine 13(2020), 2 vom: 28. Dez. volume:13 year:2020 number:2 day:28 month:12 |
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Enthalten in EMBO Molecular Medicine 13(2020), 2 vom: 28. Dez. volume:13 year:2020 number:2 day:28 month:12 |
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argininosuccinic aciduria autophagy OTC deficiency Tat‐Beclin‐1 peptide urea cycle disorders |
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Soria, Leandro R @@aut@@ Gurung, Sonam @@aut@@ De Sabbata, Giulia @@aut@@ Perocheau, Dany P @@aut@@ De Angelis, Angela @@aut@@ Bruno, Gemma @@aut@@ Polishchuk, Elena @@aut@@ Paris, Debora @@aut@@ Cuomo, Paola @@aut@@ Motta, Andrea @@aut@@ Orford, Michael @@aut@@ Khalil, Youssef @@aut@@ Eaton, Simon @@aut@@ Mills, Philippa B @@aut@@ Waddington, Simon N @@aut@@ Settembre, Carmine @@aut@@ Muro, Andrés F @@aut@@ Baruteau, Julien @@aut@@ Brunetti‐Pierri, Nicola @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058031332</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241024065233.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241024s2020 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/emmm.202013158</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058031332</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)emmm.202013158-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Soria, Leandro R</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-7124-856X</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2020</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">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.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. Beclin‐1 is a central player in autophagy and a knock‐in mouse model carrying a Becn1 mutation resulting in constitutively active autophagy shows enhanced ureagenesis and increased ammonia detoxification.TB‐1 improves biochemical abnormalities and increases survival of mice with OTC deficiency (proximal urea cycle disorder).TB‐1 improves biochemical abnormalities and survival of mice with ASL deficiency (distal urea cycle disorder).ASL deficient mice show cytoplasmic and nuclear glycogen accumulation that are both reduced by TB‐1.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea 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Soria, Leandro R |
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Soria, Leandro R misc argininosuccinic aciduria misc autophagy misc OTC deficiency misc Tat‐Beclin‐1 peptide misc urea cycle disorders Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
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Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders argininosuccinic aciduria (dpeaa)DE-He213 autophagy (dpeaa)DE-He213 OTC deficiency (dpeaa)DE-He213 Tat‐Beclin‐1 peptide (dpeaa)DE-He213 urea cycle disorders (dpeaa)DE-He213 |
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misc argininosuccinic aciduria misc autophagy misc OTC deficiency misc Tat‐Beclin‐1 peptide misc urea cycle disorders |
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Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
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(DE-627)SPR058031332 (SPR)emmm.202013158-e |
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Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
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Soria, Leandro R |
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EMBO Molecular Medicine |
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EMBO Molecular Medicine |
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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 Brunetti‐Pierri, Nicola |
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Elektronische Aufsätze |
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Soria, Leandro R |
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10.15252/emmm.202013158 |
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beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
| title_auth |
Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
| abstract |
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. Synopsis Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. Beclin‐1 is a central player in autophagy and a knock‐in mouse model carrying a Becn1 mutation resulting in constitutively active autophagy shows enhanced ureagenesis and increased ammonia detoxification.TB‐1 improves biochemical abnormalities and increases survival of mice with OTC deficiency (proximal urea cycle disorder).TB‐1 improves biochemical abnormalities and survival of mice with ASL deficiency (distal urea cycle disorder).ASL deficient mice show cytoplasmic and nuclear glycogen accumulation that are both reduced by TB‐1. Graphical Abstract Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. © The Author(s) 2020 |
| abstractGer |
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. Synopsis Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. Beclin‐1 is a central player in autophagy and a knock‐in mouse model carrying a Becn1 mutation resulting in constitutively active autophagy shows enhanced ureagenesis and increased ammonia detoxification.TB‐1 improves biochemical abnormalities and increases survival of mice with OTC deficiency (proximal urea cycle disorder).TB‐1 improves biochemical abnormalities and survival of mice with ASL deficiency (distal urea cycle disorder).ASL deficient mice show cytoplasmic and nuclear glycogen accumulation that are both reduced by TB‐1. Graphical Abstract Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. © The Author(s) 2020 |
| abstract_unstemmed |
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. Synopsis Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. Beclin‐1 is a central player in autophagy and a knock‐in mouse model carrying a Becn1 mutation resulting in constitutively active autophagy shows enhanced ureagenesis and increased ammonia detoxification.TB‐1 improves biochemical abnormalities and increases survival of mice with OTC deficiency (proximal urea cycle disorder).TB‐1 improves biochemical abnormalities and survival of mice with ASL deficiency (distal urea cycle disorder).ASL deficient mice show cytoplasmic and nuclear glycogen accumulation that are both reduced by TB‐1. Graphical Abstract Using mice with constitutive activation of autophagy and treating mice deficient for ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) with the autophagy inducing Tat‐Beclin‐1 (TB‐1), this study shows that Beclin‐1‐dependent activation of autophagy improves the phenotypes of proximal and distal defects of the urea cycle. © The Author(s) 2020 |
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Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders |
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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 Brunetti‐Pierri, Nicola |
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| score |
7.3985195 |