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Deficiency of ALADIN Impairs Redox Homeostasis in Human Adrenal Cells and Inhibits Steroidogenesis

Triple A syndrome is a rare, autosomal recessive cause of adrenal failure. Additional features include alacrima, achalasia of the esophageal cardia, and progressive neurodegenerative disease. The AAAS gene product is the nuclear pore complex protein alacrima-achalasia-adrenal insufficiency neurologi...

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Autores principales: Prasad, R., Metherell, L. A., Clark, A. J., Storr, H. L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958737/
https://www.ncbi.nlm.nih.gov/pubmed/23825130
http://dx.doi.org/10.1210/en.2013-1241
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author Prasad, R.
Metherell, L. A.
Clark, A. J.
Storr, H. L.
author_facet Prasad, R.
Metherell, L. A.
Clark, A. J.
Storr, H. L.
author_sort Prasad, R.
collection PubMed
description Triple A syndrome is a rare, autosomal recessive cause of adrenal failure. Additional features include alacrima, achalasia of the esophageal cardia, and progressive neurodegenerative disease. The AAAS gene product is the nuclear pore complex protein alacrima-achalasia-adrenal insufficiency neurological disorder (ALADIN), of unknown function. Triple A syndrome patient dermal fibroblasts appear to be more sensitive to oxidative stress than wild-type fibroblasts. To provide an adrenal and neuronal-specific disease model, we established AAAS-gene knockdown in H295R human adrenocortical tumor cells and SH-SY5Y human neuroblastoma cells by lentiviral short hairpin RNA transduction. AAAS-knockdown significantly reduced cell viability in H295R cells. This effect was exacerbated by hydrogen peroxide treatment and improved by application of the antioxidant N-acetylcysteine. An imbalance in redox homeostasis after AAAS knockdown was further suggested in the H295R cells by a decrease in the ratio of reduced to oxidized glutathione. AAAS-knockdown SH-SY5Y cells were also hypersensitive to oxidative stress and responded to antioxidant treatment. A further impact on function was observed in the AAAS-knockdown H295R cells with reduced expression of key components of the steroidogenic pathway, including steroidogenic acute regulatory and P450c11β protein expression. Importantly a significant reduction in cortisol production was demonstrated with AAAS knockdown, which was partially reversed with N-acetylcysteine treatment. Conclusion: Our in vitro data in AAAS-knockdown adrenal and neuronal cells not only corroborates previous studies implicating oxidative stress in this disorder but also provides further insights into the pathogenic mechanisms in triple A syndrome.
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spelling pubmed-39587372014-04-02 Deficiency of ALADIN Impairs Redox Homeostasis in Human Adrenal Cells and Inhibits Steroidogenesis Prasad, R. Metherell, L. A. Clark, A. J. Storr, H. L. Endocrinology Glucocorticoids-CRH-ACTH-Adrenal Triple A syndrome is a rare, autosomal recessive cause of adrenal failure. Additional features include alacrima, achalasia of the esophageal cardia, and progressive neurodegenerative disease. The AAAS gene product is the nuclear pore complex protein alacrima-achalasia-adrenal insufficiency neurological disorder (ALADIN), of unknown function. Triple A syndrome patient dermal fibroblasts appear to be more sensitive to oxidative stress than wild-type fibroblasts. To provide an adrenal and neuronal-specific disease model, we established AAAS-gene knockdown in H295R human adrenocortical tumor cells and SH-SY5Y human neuroblastoma cells by lentiviral short hairpin RNA transduction. AAAS-knockdown significantly reduced cell viability in H295R cells. This effect was exacerbated by hydrogen peroxide treatment and improved by application of the antioxidant N-acetylcysteine. An imbalance in redox homeostasis after AAAS knockdown was further suggested in the H295R cells by a decrease in the ratio of reduced to oxidized glutathione. AAAS-knockdown SH-SY5Y cells were also hypersensitive to oxidative stress and responded to antioxidant treatment. A further impact on function was observed in the AAAS-knockdown H295R cells with reduced expression of key components of the steroidogenic pathway, including steroidogenic acute regulatory and P450c11β protein expression. Importantly a significant reduction in cortisol production was demonstrated with AAAS knockdown, which was partially reversed with N-acetylcysteine treatment. Conclusion: Our in vitro data in AAAS-knockdown adrenal and neuronal cells not only corroborates previous studies implicating oxidative stress in this disorder but also provides further insights into the pathogenic mechanisms in triple A syndrome. Endocrine Society 2013-09 2013-07-03 /pmc/articles/PMC3958737/ /pubmed/23825130 http://dx.doi.org/10.1210/en.2013-1241 Text en Copyright © 2013 by The Endocrine Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/us/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Glucocorticoids-CRH-ACTH-Adrenal
Prasad, R.
Metherell, L. A.
Clark, A. J.
Storr, H. L.
Deficiency of ALADIN Impairs Redox Homeostasis in Human Adrenal Cells and Inhibits Steroidogenesis
title Deficiency of ALADIN Impairs Redox Homeostasis in Human Adrenal Cells and Inhibits Steroidogenesis
title_full Deficiency of ALADIN Impairs Redox Homeostasis in Human Adrenal Cells and Inhibits Steroidogenesis
title_fullStr Deficiency of ALADIN Impairs Redox Homeostasis in Human Adrenal Cells and Inhibits Steroidogenesis
title_full_unstemmed Deficiency of ALADIN Impairs Redox Homeostasis in Human Adrenal Cells and Inhibits Steroidogenesis
title_short Deficiency of ALADIN Impairs Redox Homeostasis in Human Adrenal Cells and Inhibits Steroidogenesis
title_sort deficiency of aladin impairs redox homeostasis in human adrenal cells and inhibits steroidogenesis
topic Glucocorticoids-CRH-ACTH-Adrenal
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958737/
https://www.ncbi.nlm.nih.gov/pubmed/23825130
http://dx.doi.org/10.1210/en.2013-1241
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