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GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress

Loss-of-function mutations in the retinal degeneration 3 (RD3) gene cause inherited retinopathy with impaired rod and cone function and fast retinal degeneration in patients and in the natural strain of rd3 mice. The underlying physiopathology mechanisms are not well understood. We previously propos...

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Autores principales: Plana-Bonamaisó, Anna, López-Begines, Santiago, Andilla, Jordi, Fidalgo, María José, Loza-Alvarez, Pablo, Estanyol, Josep María, Villa, Pedro de la, Méndez, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981271/
https://www.ncbi.nlm.nih.gov/pubmed/31980596
http://dx.doi.org/10.1038/s41419-020-2255-0
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author Plana-Bonamaisó, Anna
López-Begines, Santiago
Andilla, Jordi
Fidalgo, María José
Loza-Alvarez, Pablo
Estanyol, Josep María
Villa, Pedro de la
Méndez, Ana
author_facet Plana-Bonamaisó, Anna
López-Begines, Santiago
Andilla, Jordi
Fidalgo, María José
Loza-Alvarez, Pablo
Estanyol, Josep María
Villa, Pedro de la
Méndez, Ana
author_sort Plana-Bonamaisó, Anna
collection PubMed
description Loss-of-function mutations in the retinal degeneration 3 (RD3) gene cause inherited retinopathy with impaired rod and cone function and fast retinal degeneration in patients and in the natural strain of rd3 mice. The underlying physiopathology mechanisms are not well understood. We previously proposed that guanylate cyclase-activating proteins (GCAPs) might be key Ca(2+)-sensors mediating the physiopathology of this disorder, based on the demonstrated toxicity of GCAP2 when blocked in its Ca(2+)-free form at photoreceptor inner segments. We here show that the retinal degeneration in rd3 mice is substantially delayed by GCAPs ablation. While the number of retinal photoreceptor cells is halved in 6 weeks in rd3 mice, it takes 8 months to halve in rd3/rd3 GCAPs(−/−) mice. Although this substantial morphological rescue does not correlate with recovery of visual function due to very diminished guanylate cyclase activity in rd3 mice, it is very informative of the mechanisms underlying photoreceptor cell death. By showing that GCAP2 is mostly in its Ca(2+)-free-phosphorylated state in rd3 mice, we infer that the [Ca(2+)](i) at rod inner segments is permanently low. GCAPs are therefore retained at the inner segment in their Ca(2+)-free, guanylate cyclase activator state. We show that in this conformational state GCAPs induce endoplasmic reticulum (ER) stress, mitochondrial swelling, and cell death. ER stress and mitochondrial swelling are early hallmarks of rd3 retinas preceding photoreceptor cell death, that are substantially rescued by GCAPs ablation. By revealing the involvement of GCAPs-induced ER stress in the physiopathology of Leber’s congenital amaurosis 12 (LCA12), this work will aid to guide novel therapies to preserve retinal integrity in LCA12 patients to expand the window for gene therapy intervention to restore vision.
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spelling pubmed-69812712020-01-27 GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress Plana-Bonamaisó, Anna López-Begines, Santiago Andilla, Jordi Fidalgo, María José Loza-Alvarez, Pablo Estanyol, Josep María Villa, Pedro de la Méndez, Ana Cell Death Dis Article Loss-of-function mutations in the retinal degeneration 3 (RD3) gene cause inherited retinopathy with impaired rod and cone function and fast retinal degeneration in patients and in the natural strain of rd3 mice. The underlying physiopathology mechanisms are not well understood. We previously proposed that guanylate cyclase-activating proteins (GCAPs) might be key Ca(2+)-sensors mediating the physiopathology of this disorder, based on the demonstrated toxicity of GCAP2 when blocked in its Ca(2+)-free form at photoreceptor inner segments. We here show that the retinal degeneration in rd3 mice is substantially delayed by GCAPs ablation. While the number of retinal photoreceptor cells is halved in 6 weeks in rd3 mice, it takes 8 months to halve in rd3/rd3 GCAPs(−/−) mice. Although this substantial morphological rescue does not correlate with recovery of visual function due to very diminished guanylate cyclase activity in rd3 mice, it is very informative of the mechanisms underlying photoreceptor cell death. By showing that GCAP2 is mostly in its Ca(2+)-free-phosphorylated state in rd3 mice, we infer that the [Ca(2+)](i) at rod inner segments is permanently low. GCAPs are therefore retained at the inner segment in their Ca(2+)-free, guanylate cyclase activator state. We show that in this conformational state GCAPs induce endoplasmic reticulum (ER) stress, mitochondrial swelling, and cell death. ER stress and mitochondrial swelling are early hallmarks of rd3 retinas preceding photoreceptor cell death, that are substantially rescued by GCAPs ablation. By revealing the involvement of GCAPs-induced ER stress in the physiopathology of Leber’s congenital amaurosis 12 (LCA12), this work will aid to guide novel therapies to preserve retinal integrity in LCA12 patients to expand the window for gene therapy intervention to restore vision. Nature Publishing Group UK 2020-01-24 /pmc/articles/PMC6981271/ /pubmed/31980596 http://dx.doi.org/10.1038/s41419-020-2255-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Plana-Bonamaisó, Anna
López-Begines, Santiago
Andilla, Jordi
Fidalgo, María José
Loza-Alvarez, Pablo
Estanyol, Josep María
Villa, Pedro de la
Méndez, Ana
GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress
title GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress
title_full GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress
title_fullStr GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress
title_full_unstemmed GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress
title_short GCAP neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of LCA12 congenital blindness by involving endoplasmic reticulum stress
title_sort gcap neuronal calcium sensor proteins mediate photoreceptor cell death in the rd3 mouse model of lca12 congenital blindness by involving endoplasmic reticulum stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981271/
https://www.ncbi.nlm.nih.gov/pubmed/31980596
http://dx.doi.org/10.1038/s41419-020-2255-0
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