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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2013
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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. |
format | Online Article Text |
id | pubmed-3958737 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
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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