Assessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death

Abstract Excitotoxicity leads to the activation of a cytotoxic cascade that causes neuronal death. In the retina, retinal ganglion cells (RGCs) die after an excitotoxic insult. Multiple pathways have been proposed to contribute to RGC death after an excitotoxic insult, including TNF signaling, JNK a...

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Autores principales:	Berkeley K. Fahrenthold, Kimberly A. Fernandes, Richard T. Libby
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/83317f3ff5434210b4ad64e85fa607aa
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spelling	oai:doaj.org-article:83317f3ff5434210b4ad64e85fa607aa2021-12-02T15:05:30ZAssessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death10.1038/s41598-018-22848-y2045-2322https://doaj.org/article/83317f3ff5434210b4ad64e85fa607aa2018-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-22848-yhttps://doaj.org/toc/2045-2322Abstract Excitotoxicity leads to the activation of a cytotoxic cascade that causes neuronal death. In the retina, retinal ganglion cells (RGCs) die after an excitotoxic insult. Multiple pathways have been proposed to contribute to RGC death after an excitotoxic insult, including TNF signaling, JNK activation, and ER stress. To test the importance of these pathways in RGC death after excitotoxic injury, the excitotoxin N-methyl-D-aspartate (NMDA) was intravitreally injected into mice deficient in components of these pathways. Absence of Tnf or its canonical downstream mediator, Bid, did not confer short- or long-term protection to RGCs. Despite known activation in RGCs and a prominent role in mediating RGC death after other insults, attenuating JNK signaling did not prevent RGC death after excitotoxic insult. Additionally, deficiency of the ER stress protein DDIT3 (CHOP), which has been shown to be involved in RGC death, did not lessen NMDA induced RGC death. Furthermore, absence of both Jun (JNK’s canonical target) and Ddit3, which together provide robust, long-term protection to RGC somas after axonal insult, did not lessen RGC death. Collectively, these results indicate that the drivers of excitotoxic injury remain to be identified and/or multiple cell death pathways are activated in response to injury.Berkeley K. FahrentholdKimberly A. FernandesRichard T. LibbyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Berkeley K. Fahrenthold Kimberly A. Fernandes Richard T. Libby Assessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death
description	Abstract Excitotoxicity leads to the activation of a cytotoxic cascade that causes neuronal death. In the retina, retinal ganglion cells (RGCs) die after an excitotoxic insult. Multiple pathways have been proposed to contribute to RGC death after an excitotoxic insult, including TNF signaling, JNK activation, and ER stress. To test the importance of these pathways in RGC death after excitotoxic injury, the excitotoxin N-methyl-D-aspartate (NMDA) was intravitreally injected into mice deficient in components of these pathways. Absence of Tnf or its canonical downstream mediator, Bid, did not confer short- or long-term protection to RGCs. Despite known activation in RGCs and a prominent role in mediating RGC death after other insults, attenuating JNK signaling did not prevent RGC death after excitotoxic insult. Additionally, deficiency of the ER stress protein DDIT3 (CHOP), which has been shown to be involved in RGC death, did not lessen NMDA induced RGC death. Furthermore, absence of both Jun (JNK’s canonical target) and Ddit3, which together provide robust, long-term protection to RGC somas after axonal insult, did not lessen RGC death. Collectively, these results indicate that the drivers of excitotoxic injury remain to be identified and/or multiple cell death pathways are activated in response to injury.
format	article
author	Berkeley K. Fahrenthold Kimberly A. Fernandes Richard T. Libby
author_facet	Berkeley K. Fahrenthold Kimberly A. Fernandes Richard T. Libby
author_sort	Berkeley K. Fahrenthold
title	Assessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death
title_short	Assessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death
title_full	Assessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death
title_fullStr	Assessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death
title_full_unstemmed	Assessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death
title_sort	assessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/83317f3ff5434210b4ad64e85fa607aa
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_version_	1718388842875060224

Assessment of intrinsic and extrinsic signaling pathway in excitotoxic retinal ganglion cell death

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