Cargando…

HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice

Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially una...

Descripción completa

Detalles Bibliográficos
Autores principales: Samardzija, Marijana, Corna, Andrea, Gomez-Sintes, Raquel, Jarboui, Mohamed Ali, Armento, Angela, Roger, Jerome E., Petridou, Eleni, Haq, Wadood, Paquet-Durand, Francois, Zrenner, Eberhart, de la Villa, Pedro, Zeck, Günther, Grimm, Christian, Boya, Patricia, Ueffing, Marius, Trifunović, Dragana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026998/
https://www.ncbi.nlm.nih.gov/pubmed/33159184
http://dx.doi.org/10.1038/s41418-020-00653-3
_version_ 1783675737219268608
author Samardzija, Marijana
Corna, Andrea
Gomez-Sintes, Raquel
Jarboui, Mohamed Ali
Armento, Angela
Roger, Jerome E.
Petridou, Eleni
Haq, Wadood
Paquet-Durand, Francois
Zrenner, Eberhart
de la Villa, Pedro
Zeck, Günther
Grimm, Christian
Boya, Patricia
Ueffing, Marius
Trifunović, Dragana
author_facet Samardzija, Marijana
Corna, Andrea
Gomez-Sintes, Raquel
Jarboui, Mohamed Ali
Armento, Angela
Roger, Jerome E.
Petridou, Eleni
Haq, Wadood
Paquet-Durand, Francois
Zrenner, Eberhart
de la Villa, Pedro
Zeck, Günther
Grimm, Christian
Boya, Patricia
Ueffing, Marius
Trifunović, Dragana
author_sort Samardzija, Marijana
collection PubMed
description Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways, including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages.
format Online
Article
Text
id pubmed-8026998
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-80269982021-04-21 HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice Samardzija, Marijana Corna, Andrea Gomez-Sintes, Raquel Jarboui, Mohamed Ali Armento, Angela Roger, Jerome E. Petridou, Eleni Haq, Wadood Paquet-Durand, Francois Zrenner, Eberhart de la Villa, Pedro Zeck, Günther Grimm, Christian Boya, Patricia Ueffing, Marius Trifunović, Dragana Cell Death Differ Article Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of high acuity and color vision and, ultimately to blindness. In RP, a vast number of mutations perturb the structure and function of rod photoreceptors, while cones remain initially unaffected. Extensive rod loss in advanced stages of the disease triggers cone death by a mechanism that is still largely unknown. Here, we show that secondary cone cell death in animal models for RP is associated with increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at late stages of the disease, when the majority of rods have already degenerated, was sufficient to delay cone death and support long-term cone survival in two mouse models for RP, affected by mutations in the phosphodiesterase 6b gene. Moreover, the surviving cones remained light-sensitive, leading to an improvement in visual function. RNA-seq analysis of protected cones demonstrated that HDAC inhibition initiated multi-level protection via regulation of different pro-survival pathways, including MAPK, PI3K-Akt, and autophagy. This study suggests a unique opportunity for targeted pharmacological protection of secondary dying cones by HDAC inhibition and creates hope to maintain vision in RP patients even in advanced disease stages. Nature Publishing Group UK 2020-11-06 2021-04 /pmc/articles/PMC8026998/ /pubmed/33159184 http://dx.doi.org/10.1038/s41418-020-00653-3 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
Samardzija, Marijana
Corna, Andrea
Gomez-Sintes, Raquel
Jarboui, Mohamed Ali
Armento, Angela
Roger, Jerome E.
Petridou, Eleni
Haq, Wadood
Paquet-Durand, Francois
Zrenner, Eberhart
de la Villa, Pedro
Zeck, Günther
Grimm, Christian
Boya, Patricia
Ueffing, Marius
Trifunović, Dragana
HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice
title HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice
title_full HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice
title_fullStr HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice
title_full_unstemmed HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice
title_short HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice
title_sort hdac inhibition ameliorates cone survival in retinitis pigmentosa mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026998/
https://www.ncbi.nlm.nih.gov/pubmed/33159184
http://dx.doi.org/10.1038/s41418-020-00653-3
work_keys_str_mv AT samardzijamarijana hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT cornaandrea hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT gomezsintesraquel hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT jarbouimohamedali hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT armentoangela hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT rogerjeromee hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT petridoueleni hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT haqwadood hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT paquetdurandfrancois hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT zrennereberhart hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT delavillapedro hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT zeckgunther hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT grimmchristian hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT boyapatricia hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT ueffingmarius hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice
AT trifunovicdragana hdacinhibitionamelioratesconesurvivalinretinitispigmentosamice