Beclin‐1‐mediated activation of autophagy improves proximal and distal urea cycle disorders

Autor: Simon N. Waddington, Julien Baruteau, Andrea Motta, Gemma Bruno, Carmine Settembre, Youssef Khalil, Andrés F. Muro, Simon Eaton, Leandro R. Soria, Giulia De Sabbata, Elena Polishchuk, Michael Orford, Nicola Brunetti-Pierri, Debora Paris, Sonam Gurung, Philippa B. Mills, Dany P. Perocheau, Paola Cuomo, Angela De Angelis
Přispěvatelé: Soria, L. R., Gurung, S., De Sabbata, G., Perocheau, D. P., De Angelis, A., Bruno, G., Polishchuk, E., Paris, D., Cuomo, P., Motta, A., Orford, M., Khalil, Y., Eaton, S., Mills, P. B., Waddington, S. N., Settembre, C., Muro, A. F., Baruteau, J., Brunetti Pierri, N.
Rok vydání: 2020
Předmět:
0301 basic medicine
Medicine (General)
autophagy
medicine.medical_specialty
Orotic acid
Urinary system
Cell
Ornithine transcarbamylase
QH426-470
Pharmacology
Article
Mice
03 medical and health sciences
R5-920
0302 clinical medicine
argininosuccinic aciduria
Internal medicine
Genetics
medicine
Animals
Urea Cycle Disorders
Inborn
Tat-Beclin-1 peptide
business.industry
Autophagy
OTC deficiency
Hyperammonemia
Articles
urea cycle disorders
medicine.disease
Argininosuccinate lyase
Ornithine Carbamoyltransferase Deficiency Disease
Tat‐Beclin‐1 peptide
medicine.anatomical_structure
030104 developmental biology
Endocrinology
Argininosuccinic aciduria
Urea cycle
Molecular Medicine
Autophagy & Cell Death
Beclin-1
Genetics
Gene Therapy & Genetic Disease
business
030217 neurology & neurosurgery
medicine.drug
Zdroj: EMBO molecular medicine
e13158 (2021). doi:10.15252/emmm.202013158
info:cnr-pdr/source/autori:Soria L.R.; Gurung S.; De Sabbata G.; Perocheau D.P.; De Angelis A.; Bruno G.; Polishchuk E.; Paris D.; Cuomo P.; Motta A.; Orford M.; Khalil Y.; Eaton S.; Mills P.B.; Waddington S.N.; Settembre C.; Muro A.F.; Baruteau J.; Brunetti-Pierri N./titolo:Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders/doi:10.15252%2Femmm.202013158/rivista:EMBO molecular medicine (Print)/anno:2021/pagina_da:/pagina_a:/intervallo_pagine:/volume:e13158
EMBO Molecular Medicine
EMBO Molecular Medicine, Vol 13, Iss 2, Pp n/a-n/a (2021)
ISSN: 1757-4684
1757-4676
Popis: 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.
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.
Databáze: OpenAIRE
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