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Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke

Objective: Brain ischemia leads to the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) lumen and consequently, ER stress. To help cells restore ER function, a series of adaptive stress response pathways, collectively termed the unfolded protein response (UPR), are activ...

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Autores principales: Li, Xuan, Li, Ran, Lu, Liping, Dhar, Ashis, Sheng, Huaxin, Yang, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9614111/
https://www.ncbi.nlm.nih.gov/pubmed/36313623
http://dx.doi.org/10.3389/fncel.2022.1016391
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author Li, Xuan
Li, Ran
Lu, Liping
Dhar, Ashis
Sheng, Huaxin
Yang, Wei
author_facet Li, Xuan
Li, Ran
Lu, Liping
Dhar, Ashis
Sheng, Huaxin
Yang, Wei
author_sort Li, Xuan
collection PubMed
description Objective: Brain ischemia leads to the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) lumen and consequently, ER stress. To help cells restore ER function, a series of adaptive stress response pathways, collectively termed the unfolded protein response (UPR), are activated. We have previously demonstrated that the UPR pathway initiated by ATF6 is pro-survival in transient ischemic stroke. However, the effect of ATF6 activation on the outcome after permanent ischemic stroke remains unknown. Here, we addressed this knowledge gap. Method: sATF6-KI mice with functional short-form ATF6 (sATF6) predominantly expressed in forebrain neurons were subjected to two ischemic stroke models: photothrombotic stroke and permanent middle cerebral artery occlusion (pMCAO). Both short-term and long-term functional outcomes were evaluated. Changes in neuroinflammation and cerebrovascular density after pMCAO were also assessed. Results: Compared to littermate controls, sATF6-KI mice performed significantly better in open field, cylinder, and foot fault tests on day 1 or 3 after photothrombotic stroke. However, on days 7 and 14 after stroke, the performance of these functional tests was not significantly different between groups, which is likely related to mild brain damage associated with this stroke model. Thus, to evaluate the long-term effects of ATF6 activation in permanent stroke, we turned to our pMCAO model. We first found that on day 4 after pMCAO, functional outcome was better, and infarct volumes were smaller in sATF6-KI mice vs controls. Next, the 15-day stroke outcome study indicated that compared to control mice, sATF6-KI mice consistently exhibited improved performance in neurologic scoring, tight rope test, and tape removal test, after pMCAO. Moreover, sATF6-KI mice showed higher vascular density and lower activation of both astrocytes and microglia around stroke regions on day 16 after pMCAO. Conclusions: Here, we presented the first evidence that activation of the ATF6 UPR branch is protective in permanent ischemic stroke, which further supports the therapeutic potential of targeting the ATF6 pathway in stroke.
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spelling pubmed-96141112022-10-29 Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke Li, Xuan Li, Ran Lu, Liping Dhar, Ashis Sheng, Huaxin Yang, Wei Front Cell Neurosci Cellular Neuroscience Objective: Brain ischemia leads to the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) lumen and consequently, ER stress. To help cells restore ER function, a series of adaptive stress response pathways, collectively termed the unfolded protein response (UPR), are activated. We have previously demonstrated that the UPR pathway initiated by ATF6 is pro-survival in transient ischemic stroke. However, the effect of ATF6 activation on the outcome after permanent ischemic stroke remains unknown. Here, we addressed this knowledge gap. Method: sATF6-KI mice with functional short-form ATF6 (sATF6) predominantly expressed in forebrain neurons were subjected to two ischemic stroke models: photothrombotic stroke and permanent middle cerebral artery occlusion (pMCAO). Both short-term and long-term functional outcomes were evaluated. Changes in neuroinflammation and cerebrovascular density after pMCAO were also assessed. Results: Compared to littermate controls, sATF6-KI mice performed significantly better in open field, cylinder, and foot fault tests on day 1 or 3 after photothrombotic stroke. However, on days 7 and 14 after stroke, the performance of these functional tests was not significantly different between groups, which is likely related to mild brain damage associated with this stroke model. Thus, to evaluate the long-term effects of ATF6 activation in permanent stroke, we turned to our pMCAO model. We first found that on day 4 after pMCAO, functional outcome was better, and infarct volumes were smaller in sATF6-KI mice vs controls. Next, the 15-day stroke outcome study indicated that compared to control mice, sATF6-KI mice consistently exhibited improved performance in neurologic scoring, tight rope test, and tape removal test, after pMCAO. Moreover, sATF6-KI mice showed higher vascular density and lower activation of both astrocytes and microglia around stroke regions on day 16 after pMCAO. Conclusions: Here, we presented the first evidence that activation of the ATF6 UPR branch is protective in permanent ischemic stroke, which further supports the therapeutic potential of targeting the ATF6 pathway in stroke. Frontiers Media S.A. 2022-10-14 /pmc/articles/PMC9614111/ /pubmed/36313623 http://dx.doi.org/10.3389/fncel.2022.1016391 Text en Copyright © 2022 Li, Li, Lu, Dhar, Sheng and Yang. https://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 Cellular Neuroscience
Li, Xuan
Li, Ran
Lu, Liping
Dhar, Ashis
Sheng, Huaxin
Yang, Wei
Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke
title Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke
title_full Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke
title_fullStr Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke
title_full_unstemmed Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke
title_short Beneficial effects of neuronal ATF6 activation in permanent ischemic stroke
title_sort beneficial effects of neuronal atf6 activation in permanent ischemic stroke
topic Cellular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9614111/
https://www.ncbi.nlm.nih.gov/pubmed/36313623
http://dx.doi.org/10.3389/fncel.2022.1016391
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