Calcineurin β protects brain after injury by activating the unfolded protein response
The Ca2+-dependent phosphatase, calcineurin (CN) is thought to play a detrimental role in damaged neurons; however, its role in astrocytes is unclear. In cultured astrocytes, CNβ expression increased after treatment with a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, thapsigargin, and with oxy...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-10-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996116301449 |
| _version_ | 1818724393635807232 |
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| author | Yanan Chen Deborah M. Holstein Sofia Aime Mariana Bollo James D. Lechleiter |
| author_facet | Yanan Chen Deborah M. Holstein Sofia Aime Mariana Bollo James D. Lechleiter |
| author_sort | Yanan Chen |
| collection | DOAJ |
| description | The Ca2+-dependent phosphatase, calcineurin (CN) is thought to play a detrimental role in damaged neurons; however, its role in astrocytes is unclear. In cultured astrocytes, CNβ expression increased after treatment with a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, thapsigargin, and with oxygen and glucose deprivation, an in vitro model of ischemia. Similarly, CNβ was induced in astrocytes in vivo in two different mouse models of brain injury - photothrombotic stroke and traumatic brain injury (TBI). Immunoprecipitation and chemical activation dimerization methods pointed to physical interaction of CNβ with the unfolded protein response (UPR) sensor, protein kinase RNA-like endoplasmic reticulum kinase (PERK). In accordance, induction of CNβ resulted in oligomerization and activation of PERK. Strikingly, the presence of a phosphatase inhibitor did not interfere with CNβ-mediated activation of PERK, suggesting a hitherto undiscovered non-enzymatic role for CNβ. Importantly, the cytoprotective function of CNβ was PERK-dependent both in vitro and in vivo. Loss of CNβ in vivo resulted in a significant increase in cerebral damage, and correlated with a decrease in astrocyte size, PERK activity and glial fibrillary acidic protein (GFAP) expression. Taken together, these data reveal a critical role for the CNβ-PERK axis in not only prolonging astrocyte cell survival but also in modulating astrogliosis after brain injury. |
| first_indexed | 2024-12-17T21:25:42Z |
| format | Article |
| id | doaj.art-27b59fdd071f4f2fb1bfc9ac6ec3d9ee |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T21:25:42Z |
| publishDate | 2016-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-27b59fdd071f4f2fb1bfc9ac6ec3d9ee2022-12-21T21:32:02ZengElsevierNeurobiology of Disease1095-953X2016-10-0194139156Calcineurin β protects brain after injury by activating the unfolded protein responseYanan Chen0Deborah M. Holstein1Sofia Aime2Mariana Bollo3James D. Lechleiter4Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, TX, USADepartment of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, TX, USAInstituto de Investigación Médica M y M Ferreyra, INIMEC-CONICET, Universidad Nacional de Córdoba, Córdoba, ArgentinaInstituto de Investigación Médica M y M Ferreyra, INIMEC-CONICET, Universidad Nacional de Córdoba, Córdoba, Argentina; Corresponding authors at: Department of Cellular & Structural Biology, UTHSCSA, 8403 Floyd Curl Drive San Antonio, TX 78229-3904, USA; Instituto de Investigación Médica M y M Ferreyra, INIMEC-CONICET, Universidad Nacional de Córdoba, Córdoba, Argentina.Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, TX, USA; Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, TX, USA; Corresponding authors at: Department of Cellular & Structural Biology, UTHSCSA, 8403 Floyd Curl Drive San Antonio, TX 78229-3904, USA; Instituto de Investigación Médica M y M Ferreyra, INIMEC-CONICET, Universidad Nacional de Córdoba, Córdoba, Argentina.The Ca2+-dependent phosphatase, calcineurin (CN) is thought to play a detrimental role in damaged neurons; however, its role in astrocytes is unclear. In cultured astrocytes, CNβ expression increased after treatment with a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, thapsigargin, and with oxygen and glucose deprivation, an in vitro model of ischemia. Similarly, CNβ was induced in astrocytes in vivo in two different mouse models of brain injury - photothrombotic stroke and traumatic brain injury (TBI). Immunoprecipitation and chemical activation dimerization methods pointed to physical interaction of CNβ with the unfolded protein response (UPR) sensor, protein kinase RNA-like endoplasmic reticulum kinase (PERK). In accordance, induction of CNβ resulted in oligomerization and activation of PERK. Strikingly, the presence of a phosphatase inhibitor did not interfere with CNβ-mediated activation of PERK, suggesting a hitherto undiscovered non-enzymatic role for CNβ. Importantly, the cytoprotective function of CNβ was PERK-dependent both in vitro and in vivo. Loss of CNβ in vivo resulted in a significant increase in cerebral damage, and correlated with a decrease in astrocyte size, PERK activity and glial fibrillary acidic protein (GFAP) expression. Taken together, these data reveal a critical role for the CNβ-PERK axis in not only prolonging astrocyte cell survival but also in modulating astrogliosis after brain injury.http://www.sciencedirect.com/science/article/pii/S0969996116301449CalciumStressIschemiaTraumatic brain injuryEndoplasmic reticulum |
| spellingShingle | Yanan Chen Deborah M. Holstein Sofia Aime Mariana Bollo James D. Lechleiter Calcineurin β protects brain after injury by activating the unfolded protein response Neurobiology of Disease Calcium Stress Ischemia Traumatic brain injury Endoplasmic reticulum |
| title | Calcineurin β protects brain after injury by activating the unfolded protein response |
| title_full | Calcineurin β protects brain after injury by activating the unfolded protein response |
| title_fullStr | Calcineurin β protects brain after injury by activating the unfolded protein response |
| title_full_unstemmed | Calcineurin β protects brain after injury by activating the unfolded protein response |
| title_short | Calcineurin β protects brain after injury by activating the unfolded protein response |
| title_sort | calcineurin β protects brain after injury by activating the unfolded protein response |
| topic | Calcium Stress Ischemia Traumatic brain injury Endoplasmic reticulum |
| url | http://www.sciencedirect.com/science/article/pii/S0969996116301449 |
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