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Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans
Chronic mountain sickness (CMS) is a disease that potentially threatens a large segment of high-altitude populations during extended living at altitudes above 2,500 m. Patients with CMS suffer from severe hypoxemia, excessive erythrocytosis and neurologic deficits. The cellular mechanisms underlying...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843528/ https://www.ncbi.nlm.nih.gov/pubmed/33519361 http://dx.doi.org/10.3389/fnins.2020.607711 |
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author | Zhao, Helen Lin, Jonathan Sieck, Gary Haddad, Gabriel G. |
author_facet | Zhao, Helen Lin, Jonathan Sieck, Gary Haddad, Gabriel G. |
author_sort | Zhao, Helen |
collection | PubMed |
description | Chronic mountain sickness (CMS) is a disease that potentially threatens a large segment of high-altitude populations during extended living at altitudes above 2,500 m. Patients with CMS suffer from severe hypoxemia, excessive erythrocytosis and neurologic deficits. The cellular mechanisms underlying CMS neuropathology remain unknown. We previously showed that iPSC-derived CMS neurons have altered mitochondrial dynamics and increased susceptibility to hypoxia-induced cell death. Genome analysis from the same population identified many ER stress-related genes that play an important role in hypoxia adaptation or lack thereof. In the current study, we showed that iPSC-derived CMS neurons have increased expression of ER stress markers Grp78 and XBP1s under normoxia and hyperphosphorylation of PERK under hypoxia, alleviating ER stress does not rescue the hypoxia-induced CMS neuronal cell death. Akt is a cytosolic regulator of ER stress with PERK as a direct target of Akt. CMS neurons exhibited lack of Akt activation and lack of increased Parkin expression as compared to non-CMS neurons under hypoxia. By enhancing Akt activation and Parkin overexpression, hypoxia-induced CMS neuronal cell death was reduced. Taken together, we propose that increased Akt activation protects non-CMS from hypoxia-induced cell death. In contrast, impaired adaptive mechanisms including failure to activate Akt and increase Parkin expression render CMS neurons more susceptible to hypoxia-induced cell death. |
format | Online Article Text |
id | pubmed-7843528 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-78435282021-01-30 Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans Zhao, Helen Lin, Jonathan Sieck, Gary Haddad, Gabriel G. Front Neurosci Neuroscience Chronic mountain sickness (CMS) is a disease that potentially threatens a large segment of high-altitude populations during extended living at altitudes above 2,500 m. Patients with CMS suffer from severe hypoxemia, excessive erythrocytosis and neurologic deficits. The cellular mechanisms underlying CMS neuropathology remain unknown. We previously showed that iPSC-derived CMS neurons have altered mitochondrial dynamics and increased susceptibility to hypoxia-induced cell death. Genome analysis from the same population identified many ER stress-related genes that play an important role in hypoxia adaptation or lack thereof. In the current study, we showed that iPSC-derived CMS neurons have increased expression of ER stress markers Grp78 and XBP1s under normoxia and hyperphosphorylation of PERK under hypoxia, alleviating ER stress does not rescue the hypoxia-induced CMS neuronal cell death. Akt is a cytosolic regulator of ER stress with PERK as a direct target of Akt. CMS neurons exhibited lack of Akt activation and lack of increased Parkin expression as compared to non-CMS neurons under hypoxia. By enhancing Akt activation and Parkin overexpression, hypoxia-induced CMS neuronal cell death was reduced. Taken together, we propose that increased Akt activation protects non-CMS from hypoxia-induced cell death. In contrast, impaired adaptive mechanisms including failure to activate Akt and increase Parkin expression render CMS neurons more susceptible to hypoxia-induced cell death. Frontiers Media S.A. 2021-01-15 /pmc/articles/PMC7843528/ /pubmed/33519361 http://dx.doi.org/10.3389/fnins.2020.607711 Text en Copyright © 2021 Zhao, Lin, Sieck and Haddad. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Zhao, Helen Lin, Jonathan Sieck, Gary Haddad, Gabriel G. Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans |
title | Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans |
title_full | Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans |
title_fullStr | Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans |
title_full_unstemmed | Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans |
title_short | Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans |
title_sort | neuroprotective role of akt in hypoxia adaptation in andeans |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843528/ https://www.ncbi.nlm.nih.gov/pubmed/33519361 http://dx.doi.org/10.3389/fnins.2020.607711 |
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