Exacerbated response to oxidative stress in the Retinitis Pigmentosa CerklKD/KO mouse model triggers retinal degeneration pathways upon acute light stress
The retina is particularly vulnerable to genetic and environmental alterations that generate oxidative stress and cause cellular damage in photoreceptors and other retinal neurons, eventually leading to cell death. CERKL (CERamide Kinase-Like) mutations cause Retinitis Pigmentosa and Cone-Rod Dystro...
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| Format: | Article |
| Idioma: | English |
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Elsevier
2023-10-01
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| Col·lecció: | Redox Biology |
| Matèries: | |
| Accés en línia: | http://www.sciencedirect.com/science/article/pii/S221323172300263X |
| _version_ | 1827821355330961408 |
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| author | Rocío García-Arroyo Elena B. Domènech Carlos Herrera-Úbeda Miguel A. Asensi Cristina Núñez de Arenas José M. Cuezva Jordi Garcia-Fernàndez Federico V. Pallardó Serena Mirra Gemma Marfany |
| author_facet | Rocío García-Arroyo Elena B. Domènech Carlos Herrera-Úbeda Miguel A. Asensi Cristina Núñez de Arenas José M. Cuezva Jordi Garcia-Fernàndez Federico V. Pallardó Serena Mirra Gemma Marfany |
| author_sort | Rocío García-Arroyo |
| collection | DOAJ |
| description | The retina is particularly vulnerable to genetic and environmental alterations that generate oxidative stress and cause cellular damage in photoreceptors and other retinal neurons, eventually leading to cell death. CERKL (CERamide Kinase-Like) mutations cause Retinitis Pigmentosa and Cone-Rod Dystrophy in humans, two disorders characterized by photoreceptor degeneration and progressive vision loss. CERKL is a resilience gene against oxidative stress, and its overexpression protects cells from oxidative stress-induced apoptosis. Besides, CERKL contributes to stress granule-formation and regulates mitochondrial dynamics in the retina. Using the CerklKD/KO albino mouse model, which recapitulates the human disease, we aimed to study the impact of Cerkl knockdown on stress response and activation of photoreceptor death mechanisms upon light/oxidative stress. After acute light injury, we assessed immediate or late retinal stress response, by combining both omic and non-omic approaches. Our results show that Cerkl knockdown increases ROS levels and causes a basal exacerbated stress state in the retina, through alterations in glutathione metabolism and stress granule production, overall compromising an adequate response to additional oxidative damage. As a consequence, several cell death mechanisms are triggered in CerklKD/KO retinas after acute light stress. Our studies indicate that Cerkl gene is a pivotal player in regulating light-challenged retinal homeostasis and shed light on how mutations in CERKL lead to blindness by dysregulation of the basal oxidative stress response in the retina. |
| first_indexed | 2024-03-12T01:43:14Z |
| format | Article |
| id | doaj.art-3956c7ada76a466f93445df60c4c46ff |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-12T01:43:14Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-3956c7ada76a466f93445df60c4c46ff2023-09-10T04:24:11ZengElsevierRedox Biology2213-23172023-10-0166102862Exacerbated response to oxidative stress in the Retinitis Pigmentosa CerklKD/KO mouse model triggers retinal degeneration pathways upon acute light stressRocío García-Arroyo0Elena B. Domènech1Carlos Herrera-Úbeda2Miguel A. Asensi3Cristina Núñez de Arenas4José M. Cuezva5Jordi Garcia-Fernàndez6Federico V. Pallardó7Serena Mirra8Gemma Marfany9Department of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona – Institut de Recerca Sant Joan de Déu (IBUB-IRSJD), Barcelona, Spain; Centro de Investigación Biomédica En Red (CIBER) de Enfermedades Raras (CIBERER), ISCIII, Madrid, SpainDepartment of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona – Institut de Recerca Sant Joan de Déu (IBUB-IRSJD), Barcelona, Spain; Centro de Investigación Biomédica En Red (CIBER) de Enfermedades Raras (CIBERER), ISCIII, Madrid, SpainDepartment of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona – Institut de Recerca Sant Joan de Déu (IBUB-IRSJD), Barcelona, SpainCentro de Investigación Biomédica En Red (CIBER) de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Department of Physiology, University of Valencia-INCLIVA, Valencia, SpainCentro de Investigación Biomédica En Red (CIBER) de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Departament of Molecular Biology, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre, Madrid, SpainCentro de Investigación Biomédica En Red (CIBER) de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Departament of Molecular Biology, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain; Instituto de Investigación Hospital 12 de Octubre, Madrid, SpainDepartment of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona – Institut de Recerca Sant Joan de Déu (IBUB-IRSJD), Barcelona, SpainCentro de Investigación Biomédica En Red (CIBER) de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Department of Physiology, University of Valencia-INCLIVA, Valencia, SpainDepartment of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona – Institut de Recerca Sant Joan de Déu (IBUB-IRSJD), Barcelona, Spain; Centro de Investigación Biomédica En Red (CIBER) de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Corresponding author. Department of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona, Spain.Department of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona – Institut de Recerca Sant Joan de Déu (IBUB-IRSJD), Barcelona, Spain; Centro de Investigación Biomédica En Red (CIBER) de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain; Corresponding author. Department of Genetics, Microbiology and Statistics, Universitat de Barcelona, Barcelona, Spain.The retina is particularly vulnerable to genetic and environmental alterations that generate oxidative stress and cause cellular damage in photoreceptors and other retinal neurons, eventually leading to cell death. CERKL (CERamide Kinase-Like) mutations cause Retinitis Pigmentosa and Cone-Rod Dystrophy in humans, two disorders characterized by photoreceptor degeneration and progressive vision loss. CERKL is a resilience gene against oxidative stress, and its overexpression protects cells from oxidative stress-induced apoptosis. Besides, CERKL contributes to stress granule-formation and regulates mitochondrial dynamics in the retina. Using the CerklKD/KO albino mouse model, which recapitulates the human disease, we aimed to study the impact of Cerkl knockdown on stress response and activation of photoreceptor death mechanisms upon light/oxidative stress. After acute light injury, we assessed immediate or late retinal stress response, by combining both omic and non-omic approaches. Our results show that Cerkl knockdown increases ROS levels and causes a basal exacerbated stress state in the retina, through alterations in glutathione metabolism and stress granule production, overall compromising an adequate response to additional oxidative damage. As a consequence, several cell death mechanisms are triggered in CerklKD/KO retinas after acute light stress. Our studies indicate that Cerkl gene is a pivotal player in regulating light-challenged retinal homeostasis and shed light on how mutations in CERKL lead to blindness by dysregulation of the basal oxidative stress response in the retina.http://www.sciencedirect.com/science/article/pii/S221323172300263XCERamide kinase-likeInherited retinal dystrophiesOxidative stressLight injuryStress responseRetinal degeneration |
| spellingShingle | Rocío García-Arroyo Elena B. Domènech Carlos Herrera-Úbeda Miguel A. Asensi Cristina Núñez de Arenas José M. Cuezva Jordi Garcia-Fernàndez Federico V. Pallardó Serena Mirra Gemma Marfany Exacerbated response to oxidative stress in the Retinitis Pigmentosa CerklKD/KO mouse model triggers retinal degeneration pathways upon acute light stress Redox Biology CERamide kinase-like Inherited retinal dystrophies Oxidative stress Light injury Stress response Retinal degeneration |
| title | Exacerbated response to oxidative stress in the Retinitis Pigmentosa CerklKD/KO mouse model triggers retinal degeneration pathways upon acute light stress |
| title_full | Exacerbated response to oxidative stress in the Retinitis Pigmentosa CerklKD/KO mouse model triggers retinal degeneration pathways upon acute light stress |
| title_fullStr | Exacerbated response to oxidative stress in the Retinitis Pigmentosa CerklKD/KO mouse model triggers retinal degeneration pathways upon acute light stress |
| title_full_unstemmed | Exacerbated response to oxidative stress in the Retinitis Pigmentosa CerklKD/KO mouse model triggers retinal degeneration pathways upon acute light stress |
| title_short | Exacerbated response to oxidative stress in the Retinitis Pigmentosa CerklKD/KO mouse model triggers retinal degeneration pathways upon acute light stress |
| title_sort | exacerbated response to oxidative stress in the retinitis pigmentosa cerklkd ko mouse model triggers retinal degeneration pathways upon acute light stress |
| topic | CERamide kinase-like Inherited retinal dystrophies Oxidative stress Light injury Stress response Retinal degeneration |
| url | http://www.sciencedirect.com/science/article/pii/S221323172300263X |
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