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dc.contributor.author
Platón-Corchado, María
dc.contributor.author
Barcelona, Pablo Federico
dc.contributor.author
Jmaeff, Sean
dc.contributor.author
Marchena, Miguel
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Hernández-Pinto, Alberto M.
dc.contributor.author
Hernández-Sánchez, Catalina
dc.contributor.author
Saragovi, H. Uri
dc.contributor.author
de la Rosa, Enrique J
dc.date.available
2018-06-12T18:20:13Z
dc.date.issued
2017-07
dc.identifier.citation
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
dc.identifier.issn
2041-4889
dc.identifier.uri
http://hdl.handle.net/11336/48381
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Nature Publishing Group
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
P75ntr/Prongf Axis
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Retinitis Pigmentosa (Rp)
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Photoreceptor
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Neuroprotection
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Inmunología
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Medicina Básica
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CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
p75NTR antagonists attenuate photoreceptor cell loss in murine models of retinitis pigmentosa
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-06-11T12:58:35Z
dc.journal.volume
8
dc.journal.number
7
dc.journal.pais
Reino Unido
dc.journal.ciudad
Londres
dc.description.fil
Fil: Platón-Corchado, María. Consejo Superior de Investigaciones Científicas; España
dc.description.fil
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
dc.description.fil
Fil: Jmaeff, Sean. Mc Gill University. Lady Davis Research Intitute; Canadá
dc.description.fil
Fil: Marchena, Miguel. Consejo Superior de Investigaciones Científicas; España
dc.description.fil
Fil: Hernández-Pinto, Alberto M.. Consejo Superior de Investigaciones Científicas; España
dc.description.fil
Fil: Hernández-Sánchez, Catalina. Consejo Superior de Investigaciones Científicas; España
dc.description.fil
Fil: Saragovi, H. Uri. Mc Gill University. Lady Davis Research Intitute; Canadá
dc.description.fil
Fil: de la Rosa, Enrique J. Centro de Investigaciones Biológicas; España
dc.journal.title
Cell Death and Disease
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/cddis2017306
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1038/cddis.2017.306
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