García-Arroyo, RocíoDomènech, Elena B.Herrera Úbeda, CarlosAsensi, Miguel A.Núñez de Arenas, CristinaCuezva, José M.Garcia Fernández, JordiPallardó, Federico V.Mirra, SerenaMarfany i Nadal, Gemma2024-01-262024-01-262023-10-012213-2317https://hdl.handle.net/2445/206412The 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. <em>CERKL </em>(<em>CERamide Kinase-Like</em>) mutations cause Retinitis Pigmentosa and Cone-Rod Dystrophy in humans, two disorders characterized by photoreceptor degeneration and progressive vision loss. <em>CERKL </em>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 <em>CerklKD/KO </em>albino mouse model, which recapitulates the human disease, we aimed to study the impact of <em>Cerkl </em>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 <em>Cerkl </em>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 <em>CerklKD/KO </em>retinas after acute light stress. Our studies indicate that <em>Cerkl </em>gene is a pivotal player in regulating light-challenged retinal homeostasis and shed light on how mutations in <em>CERKL </em>lead to blindness by dysregulation of the basal oxidative stress response in the retina.15 p.application/pdfengcc-by-nc-nd (c) García-Arroyo, Rocío et al., 2023http://creativecommons.org/licenses/by-nc-nd/3.0/es/Malalties de la retinaEstrès oxidatiuRetinal diseasesOxidative stressExacerbated response to oxidative stress in the Retinitis Pigmentosa CerklKD/KO mouse model triggers retinal degeneration pathways upon acute light stressinfo:eu-repo/semantics/article7393902024-01-26info:eu-repo/semantics/openAccess