Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis

Abstract Dysregulation of iron metabolism, and resultant cytotoxicity, has been implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative processes. Iron accumulation promotes cytotoxicity through various mechanisms including oxidative stress and glutamate toxicity, and o...

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Autores principales:	Reas S. Khan, Bailey Baumann, Kimberly Dine, Ying Song, Joshua L. Dunaief, Sangwon F. Kim, Kenneth S. Shindler
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d0bc350eede54e77b57423da0e937210
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spelling	oai:doaj.org-article:d0bc350eede54e77b57423da0e9372102021-12-02T15:08:07ZDexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis10.1038/s41598-019-48087-32045-2322https://doaj.org/article/d0bc350eede54e77b57423da0e9372102019-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-48087-3https://doaj.org/toc/2045-2322Abstract Dysregulation of iron metabolism, and resultant cytotoxicity, has been implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative processes. Iron accumulation promotes cytotoxicity through various mechanisms including oxidative stress and glutamate toxicity, and occurs in both MS patients and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Divalent Metal Transporter1, a major iron importer in cells, is stimulated by signaling of Dexras1, a small G protein member of the Ras family. Dexras1 is activated by S-nitrosylation by nitric oxide (NO) produced by either inducible nitric oxide synthase in activated microglia/macrophages or neuronal nitric oxide synthase in neurons. Here we show Dexras1 exacerbates oxidative stress-induced neurodegeneration in experimental optic neuritis, an inflammatory demyelinating optic nerve condition that occurs in MS and EAE. Dexras1 deletion, as well as treatment with the iron chelator deferiprone, preserves vision and attenuates retinal ganglion cell (RGC) and axonal loss during EAE optic neuritis. These results suggest that iron entry triggered by NO-activated Dexras1 signaling is a potential mechanism of neuronal death in experimental optic neuritis. The current data suggest modulation of Dexras1 signaling and iron chelation are potential novel treatment strategies for optic neuritis and MS, and possibly other optic neuropathies as well.Reas S. KhanBailey BaumannKimberly DineYing SongJoshua L. DunaiefSangwon F. KimKenneth S. ShindlerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-11 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Reas S. Khan Bailey Baumann Kimberly Dine Ying Song Joshua L. Dunaief Sangwon F. Kim Kenneth S. Shindler Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis
description	Abstract Dysregulation of iron metabolism, and resultant cytotoxicity, has been implicated in the pathogenesis of multiple sclerosis (MS) and other neurodegenerative processes. Iron accumulation promotes cytotoxicity through various mechanisms including oxidative stress and glutamate toxicity, and occurs in both MS patients and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Divalent Metal Transporter1, a major iron importer in cells, is stimulated by signaling of Dexras1, a small G protein member of the Ras family. Dexras1 is activated by S-nitrosylation by nitric oxide (NO) produced by either inducible nitric oxide synthase in activated microglia/macrophages or neuronal nitric oxide synthase in neurons. Here we show Dexras1 exacerbates oxidative stress-induced neurodegeneration in experimental optic neuritis, an inflammatory demyelinating optic nerve condition that occurs in MS and EAE. Dexras1 deletion, as well as treatment with the iron chelator deferiprone, preserves vision and attenuates retinal ganglion cell (RGC) and axonal loss during EAE optic neuritis. These results suggest that iron entry triggered by NO-activated Dexras1 signaling is a potential mechanism of neuronal death in experimental optic neuritis. The current data suggest modulation of Dexras1 signaling and iron chelation are potential novel treatment strategies for optic neuritis and MS, and possibly other optic neuropathies as well.
format	article
author	Reas S. Khan Bailey Baumann Kimberly Dine Ying Song Joshua L. Dunaief Sangwon F. Kim Kenneth S. Shindler
author_facet	Reas S. Khan Bailey Baumann Kimberly Dine Ying Song Joshua L. Dunaief Sangwon F. Kim Kenneth S. Shindler
author_sort	Reas S. Khan
title	Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis
title_short	Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis
title_full	Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis
title_fullStr	Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis
title_full_unstemmed	Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis
title_sort	dexras1 deletion and iron chelation promote neuroprotection in experimental optic neuritis
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/d0bc350eede54e77b57423da0e937210
work_keys_str_mv	AT reasskhan dexras1deletionandironchelationpromoteneuroprotectioninexperimentalopticneuritis AT baileybaumann dexras1deletionandironchelationpromoteneuroprotectioninexperimentalopticneuritis AT kimberlydine dexras1deletionandironchelationpromoteneuroprotectioninexperimentalopticneuritis AT yingsong dexras1deletionandironchelationpromoteneuroprotectioninexperimentalopticneuritis AT joshualdunaief dexras1deletionandironchelationpromoteneuroprotectioninexperimentalopticneuritis AT sangwonfkim dexras1deletionandironchelationpromoteneuroprotectioninexperimentalopticneuritis AT kennethsshindler dexras1deletionandironchelationpromoteneuroprotectioninexperimentalopticneuritis
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Dexras1 Deletion and Iron Chelation Promote Neuroprotection in Experimental Optic Neuritis

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