p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa

Autores
Platón-Corchado, María; Barcelona, Pablo Federico; Jmaeff, Sean; Marchena, Miguel; Hernández-Pinto, Alberto M.; Hernández-Sánchez, Catalina; Saragovi, H. Uri; de la Rosa, Enrique J
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
ProNGF signaling through p75NTR has been associated with neurodegenerative disorders. Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies that causes progressive photoreceptor cell degeneration and death, at a rate dependent on the genetic mutation. There are more than 300 mutations causing RP, and this is a challenge to therapy. Our study was designed to explore a common mechanism for p75NTR in the progression of RP, and assess its potential value as a therapeutic target. The proNGF/p75NTR system is present in the dystrophic retina of the rd10 RP mouse model. Compared with wild-type (WT) retina, the levels of unprocessed proNGF were increased in the rd10 retina at early degenerative stages, before the peak of photoreceptor cell death. Conversely, processed NGF levels were similar in rd10 and WT retinas. ProNGF remained elevated throughout the period of photoreceptor cell loss, correlating with increased expression of α2-macroglobulin, an inhibitor of proNGF processing. The neuroprotective effect of blocking p75NTR was assessed in organotypic retinal cultures from rd10 and RhoP mouse models. Retinal explants treated with p75NTR antagonists showed significantly reduced photoreceptor cell death, as determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and by preservation of the thickness of the outer nuclear layer (ONL), where photoreceptor nuclei are located. This effect was accompanied by decreased retinal-reactive gliosis and reduced TNFα secretion. Use of p75NTR antagonist THX-B (1,3-diisopropyl-1-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetyl]-urea) in vivo in the rd10 and RhoP mouse models, by a single intravitreal or subconjunctival injection, afforded neuroprotection to photoreceptor cells, with preservation of the ONL. This study demonstrates a role of the p75NTR/proNGF axis in the progression of RP, and validates these proteins as therapeutic targets in two different RP models, suggesting utility irrespective of etiology.
Fil: Platón-Corchado, María. Consejo Superior de Investigaciones Científicas; España
Fil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Jmaeff, Sean. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Marchena, Miguel. Consejo Superior de Investigaciones Científicas; España
Fil: Hernández-Pinto, Alberto M.. Consejo Superior de Investigaciones Científicas; España
Fil: Hernández-Sánchez, Catalina. Consejo Superior de Investigaciones Científicas; España
Fil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: de la Rosa, Enrique J. Centro de Investigaciones Biológicas; España
Materia
p75NTR/PRONGF AXIS
RETINITIS PIGMENTOSA (RP)
PHOTORECEPTOR
NEUROPROTECTION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/48381
Acceder
id CONICETDig_49d0947da0ea563a1d94470e98cd898e
oai_identifier_str oai:ri.conicet.gov.ar:11336/48381
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosaPlatón-Corchado, MaríaBarcelona, Pablo FedericoJmaeff, SeanMarchena, MiguelHernández-Pinto, Alberto M.Hernández-Sánchez, CatalinaSaragovi, H. Uride la Rosa, Enrique Jp75NTR/PRONGF AXISRETINITIS PIGMENTOSA (RP)PHOTORECEPTORNEUROPROTECTIONhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3ProNGF signaling through p75NTR has been associated with neurodegenerative disorders. Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies that causes progressive photoreceptor cell degeneration and death, at a rate dependent on the genetic mutation. There are more than 300 mutations causing RP, and this is a challenge to therapy. Our study was designed to explore a common mechanism for p75NTR in the progression of RP, and assess its potential value as a therapeutic target. The proNGF/p75NTR system is present in the dystrophic retina of the rd10 RP mouse model. Compared with wild-type (WT) retina, the levels of unprocessed proNGF were increased in the rd10 retina at early degenerative stages, before the peak of photoreceptor cell death. Conversely, processed NGF levels were similar in rd10 and WT retinas. ProNGF remained elevated throughout the period of photoreceptor cell loss, correlating with increased expression of α2-macroglobulin, an inhibitor of proNGF processing. The neuroprotective effect of blocking p75NTR was assessed in organotypic retinal cultures from rd10 and RhoP mouse models. Retinal explants treated with p75NTR antagonists showed significantly reduced photoreceptor cell death, as determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and by preservation of the thickness of the outer nuclear layer (ONL), where photoreceptor nuclei are located. This effect was accompanied by decreased retinal-reactive gliosis and reduced TNFα secretion. Use of p75NTR antagonist THX-B (1,3-diisopropyl-1-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetyl]-urea) in vivo in the rd10 and RhoP mouse models, by a single intravitreal or subconjunctival injection, afforded neuroprotection to photoreceptor cells, with preservation of the ONL. This study demonstrates a role of the p75NTR/proNGF axis in the progression of RP, and validates these proteins as therapeutic targets in two different RP models, suggesting utility irrespective of etiology.Fil: Platón-Corchado, María. Consejo Superior de Investigaciones Científicas; EspañaFil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Jmaeff, Sean. Mc Gill University. Lady Davis Research Intitute; CanadáFil: Marchena, Miguel. Consejo Superior de Investigaciones Científicas; EspañaFil: Hernández-Pinto, Alberto M.. Consejo Superior de Investigaciones Científicas; EspañaFil: Hernández-Sánchez, Catalina. Consejo Superior de Investigaciones Científicas; EspañaFil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; CanadáFil: de la Rosa, Enrique J. Centro de Investigaciones Biológicas; EspañaNature Publishing Group2017-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/48381Platón-Corchado, María; Barcelona, Pablo Federico; Jmaeff, Sean; Marchena, Miguel; Hernández-Pinto, Alberto M.; et al.; p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa; Nature Publishing Group; Cell Death and Disease; 8; 7; 7-20172041-4889CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/cddis2017306info:eu-repo/semantics/altIdentifier/doi/10.1038/cddis.2017.306info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:56:47Zoai:ri.conicet.gov.ar:11336/48381instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:56:47.665CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa
title p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa
spellingShingle p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa
Platón-Corchado, María
p75NTR/PRONGF AXIS
RETINITIS PIGMENTOSA (RP)
PHOTORECEPTOR
NEUROPROTECTION
title_short p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa
title_full p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa
title_fullStr p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa
title_full_unstemmed p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa
title_sort p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa
dc.creator.none.fl_str_mv Platón-Corchado, María
Barcelona, Pablo Federico
Jmaeff, Sean
Marchena, Miguel
Hernández-Pinto, Alberto M.
Hernández-Sánchez, Catalina
Saragovi, H. Uri
de la Rosa, Enrique J
author Platón-Corchado, María
author_facet Platón-Corchado, María
Barcelona, Pablo Federico
Jmaeff, Sean
Marchena, Miguel
Hernández-Pinto, Alberto M.
Hernández-Sánchez, Catalina
Saragovi, H. Uri
de la Rosa, Enrique J
author_role author
author2 Barcelona, Pablo Federico
Jmaeff, Sean
Marchena, Miguel
Hernández-Pinto, Alberto M.
Hernández-Sánchez, Catalina
Saragovi, H. Uri
de la Rosa, Enrique J
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv p75NTR/PRONGF AXIS
RETINITIS PIGMENTOSA (RP)
PHOTORECEPTOR
NEUROPROTECTION
topic p75NTR/PRONGF AXIS
RETINITIS PIGMENTOSA (RP)
PHOTORECEPTOR
NEUROPROTECTION
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv ProNGF signaling through p75NTR has been associated with neurodegenerative disorders. Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies that causes progressive photoreceptor cell degeneration and death, at a rate dependent on the genetic mutation. There are more than 300 mutations causing RP, and this is a challenge to therapy. Our study was designed to explore a common mechanism for p75NTR in the progression of RP, and assess its potential value as a therapeutic target. The proNGF/p75NTR system is present in the dystrophic retina of the rd10 RP mouse model. Compared with wild-type (WT) retina, the levels of unprocessed proNGF were increased in the rd10 retina at early degenerative stages, before the peak of photoreceptor cell death. Conversely, processed NGF levels were similar in rd10 and WT retinas. ProNGF remained elevated throughout the period of photoreceptor cell loss, correlating with increased expression of α2-macroglobulin, an inhibitor of proNGF processing. The neuroprotective effect of blocking p75NTR was assessed in organotypic retinal cultures from rd10 and RhoP mouse models. Retinal explants treated with p75NTR antagonists showed significantly reduced photoreceptor cell death, as determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and by preservation of the thickness of the outer nuclear layer (ONL), where photoreceptor nuclei are located. This effect was accompanied by decreased retinal-reactive gliosis and reduced TNFα secretion. Use of p75NTR antagonist THX-B (1,3-diisopropyl-1-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetyl]-urea) in vivo in the rd10 and RhoP mouse models, by a single intravitreal or subconjunctival injection, afforded neuroprotection to photoreceptor cells, with preservation of the ONL. This study demonstrates a role of the p75NTR/proNGF axis in the progression of RP, and validates these proteins as therapeutic targets in two different RP models, suggesting utility irrespective of etiology.
Fil: Platón-Corchado, María. Consejo Superior de Investigaciones Científicas; España
Fil: Barcelona, Pablo Federico. Mc Gill University. Lady Davis Research Intitute; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Jmaeff, Sean. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: Marchena, Miguel. Consejo Superior de Investigaciones Científicas; España
Fil: Hernández-Pinto, Alberto M.. Consejo Superior de Investigaciones Científicas; España
Fil: Hernández-Sánchez, Catalina. Consejo Superior de Investigaciones Científicas; España
Fil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; Canadá
Fil: de la Rosa, Enrique J. Centro de Investigaciones Biológicas; España
description ProNGF signaling through p75NTR has been associated with neurodegenerative disorders. Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies that causes progressive photoreceptor cell degeneration and death, at a rate dependent on the genetic mutation. There are more than 300 mutations causing RP, and this is a challenge to therapy. Our study was designed to explore a common mechanism for p75NTR in the progression of RP, and assess its potential value as a therapeutic target. The proNGF/p75NTR system is present in the dystrophic retina of the rd10 RP mouse model. Compared with wild-type (WT) retina, the levels of unprocessed proNGF were increased in the rd10 retina at early degenerative stages, before the peak of photoreceptor cell death. Conversely, processed NGF levels were similar in rd10 and WT retinas. ProNGF remained elevated throughout the period of photoreceptor cell loss, correlating with increased expression of α2-macroglobulin, an inhibitor of proNGF processing. The neuroprotective effect of blocking p75NTR was assessed in organotypic retinal cultures from rd10 and RhoP mouse models. Retinal explants treated with p75NTR antagonists showed significantly reduced photoreceptor cell death, as determined by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and by preservation of the thickness of the outer nuclear layer (ONL), where photoreceptor nuclei are located. This effect was accompanied by decreased retinal-reactive gliosis and reduced TNFα secretion. Use of p75NTR antagonist THX-B (1,3-diisopropyl-1-[2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-yl)-acetyl]-urea) in vivo in the rd10 and RhoP mouse models, by a single intravitreal or subconjunctival injection, afforded neuroprotection to photoreceptor cells, with preservation of the ONL. This study demonstrates a role of the p75NTR/proNGF axis in the progression of RP, and validates these proteins as therapeutic targets in two different RP models, suggesting utility irrespective of etiology.
publishDate 2017
dc.date.none.fl_str_mv 2017-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/48381
Platón-Corchado, María; Barcelona, Pablo Federico; Jmaeff, Sean; Marchena, Miguel; Hernández-Pinto, Alberto M.; et al.; p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa; Nature Publishing Group; Cell Death and Disease; 8; 7; 7-2017
2041-4889
CONICET Digital
CONICET
url http://hdl.handle.net/11336/48381
identifier_str_mv Platón-Corchado, María; Barcelona, Pablo Federico; Jmaeff, Sean; Marchena, Miguel; Hernández-Pinto, Alberto M.; et al.; p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa; Nature Publishing Group; Cell Death and Disease; 8; 7; 7-2017
2041-4889
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/cddis2017306
info:eu-repo/semantics/altIdentifier/doi/10.1038/cddis.2017.306
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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