The Thioredoxin Encoded by the Rod-Derived Cone Viability Factor Gene Protects Cone Photoreceptors Against Oxidative Stress

Xin, Mei; Chaffiol, Antoine; Kole, Christo; Yang, Ying; Millet-Puel, Géraldine; Clérin, Emmanuelle; Aït-Ali, Najate; Bennett, Jean; Dalkara, Deniz; Sahel, José‐Alain; Duebel, Jens; Léveillard, Thierry

doi:10.1089/ars.2015.6509

Cited by 43 publications

(49 citation statements)

References 37 publications

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“…32 Interestingly, we have not been able to find rings devoid of photoreceptors in an animal model of retinal degeneration induced by taurine depletion that causes primary loss of cones, 13 and it is tempting to suggest that these rings may be related to a rod-cone dependent survival mechanism. 10,[19][20][21]25,32,42,87,[88][89][90][91] The rings in our model and in other animal models 23 contain degenerating cones whose inner segments are directed towards the center of the rings. These degenerating cones show a redistribution of the opsin expression to their inner segment, soma, axons, and synaptic terminals.…”

Section: Cone Loss In Light-induced Retinal Degenerationmentioning

confidence: 78%

Coordinated Intervention of Microglial and Müller Cells in Light-Induced Retinal Degeneration

Pierdomenico

Martínez-Vacas

Hernández-Muñoz

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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To analyze the role of microglial and Müller cells in the formation of rings of photoreceptor degeneration caused by phototoxicity. METHODS. Two-month-old Sprague-Dawley rats were exposed to light and processed 1, 2, or 3 months later. Retinas were dissected as whole-mounts, immunodetected for microglial cells, Müller cells, and Sand L/M-cones and analyzed using fluorescence, thunder imaging, and confocal microscopy. Cone populations were automatically counted and isodensity maps constructed to document cone topography. RESULTS. Phototoxicity causes a significant progressive loss of Sand L/M-cones of up to 68% and 44%, respectively, at 3 months after light exposure (ALE). One month ALE, we observed rings of cone degeneration in the photosensitive area of the superior retina. Two and 3 months ALE, these rings had extended to the central and inferior retina. Within the rings of cone degeneration, there were degenerating cones, often activated microglial cells, and numerous radially oriented processes of Müller cells that showed increased expression of intermediate filaments. Between 1 and 3 months ALE, the rings coalesced, and at the same time the microglial cells resumed a mosaic-like distribution, and there was a decrease of Müller cell gliosis at the areas devoid of cones. CONCLUSIONS. Light-induced photoreceptor degeneration proceeds with rings of cone degeneration, as observed in inherited retinal degenerations in which cone death is secondary to rod degeneration. The spatiotemporal relationship of cone death microglial cell activation and Müller cell gliosis within the rings of cone degeneration suggests that, although both glial cells are involved in the formation of the rings, they may have coordinated actions and, while microglial cells may be more involved in photoreceptor phagocytosis, Müller cells may be more involved in cone and microglial cell migration, retinal remodeling and glial seal formation.

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Section: Cone Loss In Light-induced Retinal Degenerationmentioning

confidence: 78%

Coordinated Intervention of Microglial and Müller Cells in Light-Induced Retinal Degeneration

Pierdomenico

Martínez-Vacas

Hernández-Muñoz

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…3f) and increased rod function (Fig. 3a), may contribute to cone survival through rod-derived cone viability factor which promotes cone survival (Mei et al 2016). Fig.…”

Section: Discussionmentioning

confidence: 99%

Metipranolol promotes structure and function of retinal photoreceptors in the rd10 mouse model of human retinitis pigmentosa

Kanan

Khan

Lorenc

et al. 2018

Journal of Neurochemistry

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Metipranolol is a β‐adrenergic receptor antagonist that is given orally for the treatment of hypertension and also applied topically to the cornea for treating glaucoma. It also inhibits nitrosative stress which has previously been shown to be the cause of cone photoreceptor death in retinitis pigmentosa. In this study, we tested the hypothesis that metipranolol protects photoreceptor structure and function in the mouse model rd10. At P35, compared with vehicle‐treated rd10 mice in which rod degeneration was nearly complete, rd10 mice given daily subcutaneous injections of 40 mg/kg of metipranolol had reduction in markers of nitrosative stress, fewer TUNEL‐positive cells, increased outer nuclear layer thickness, and substantially more staining for rhodopsin. This was accompanied by significantly higher mean scotopic and photopic electroretinogram b‐wave amplitudes indicating improved photoreceptor function. At P50, metipranolol‐treated rd10 mice had decreased 3‐nitrotyrosine staining in the retina, increased immunostaining for cone arrestin, a marker for cone photoreceptors, and significantly higher scotopic and photopic b‐wave amplitudes at the highest stimulus intensity compared with vehicle‐treated mice. At P65, cone density was significantly higher in metipranolol‐treated versus vehicle‐injected rd10 mice. Metipranolol applied as eye drops promoted cone photoreceptor function in retinas of rd10 mice greater than subcutaneously injected metipranolol. The reduced nitrosative damage and rescue of functional loss of photoreceptors in rd10 mice suggests that metipranolol, a drug with established ocular safety and tolerability, may have potential for treating patients with retinitis pigmentosa.

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“…23 Interestingly, both these rats suffer a rhodopsin mutation that causes rod loss and secondary cone degeneration, and it is possible that these rings lacking photoreceptors may be related to a rod-conedependent survival mechanism. 66,70,[73][74][75][76][77] Indeed, healthy rods may be essential for cone survival by secreting factors such as the rod-derived cone viability factor 73,[78][79][80] and, thus, if rods die, cones may also die. This may also explain why in the nonlight-exposed taurine-depleted animals, we were not able to see rings of cone degeneration even when there is cone loss, because taurine deficiency causes cone loss before rod alteration.…”

Section: Taurine Depletion Increases Retinal Degenerationmentioning

confidence: 99%

Taurine Depletion Causes ipRGC Loss and Increases Light-Induced Photoreceptor Degeneration

García‐Ayuso

Pierdomenico

Hadj-Saïd

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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METHODS. Albino rats received b-alanine in the drinking water to induce taurine depletion. One month later, half of the animals were exposed to white light (3000 lux) continuously for 48 hours and the rest remained in normal environmental conditions. A control group of animals nontreated with b-alanine also was prepared, and half of them were exposed to light using the same protocol. All the animals were processed 2 months after the beginning of the experiment. Retinas were dissected as wholemounts and immunodetected with antibodies against Brn3a, melanopsin, S-opsin, and L-opsin to label different retinal populations: Brn3a þ retinal ganglion cells (RGCs) (image-forming RGCs), m þ RGCs (non-image-forming RGCs), and S-and L/M-cones, respectively. RESULTS. Light exposure did not affect the numbers of Brn3aþ RGCs or m þ RGCs but diminished the numbers of S-and L/M-cones and caused the appearance of rings devoid of cones, mainly in an ''arciform'' area in the superotemporal retina. Taurine depletion caused a diminution of all the studied populations, with m þ RGCs the most affected, followed by Scones. Light exposure under taurine depletion increased photoreceptor degeneration but did not seem to increase Brn3a þ RGCs or m þ RGCs loss. CONCLUSIONS.Our results document that taurine is necessary for cell survival in the rat retina and even more under light-induced photoreceptor degeneration. Thus, taurine supplementation may help to prevent retinal degenerations, especially those that commence with S-cone degeneration or in which light may be an etiologic factor, such as inherited retinal degenerations, AMD, or glaucoma.

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The Thioredoxin Encoded by the Rod-Derived Cone Viability Factor Gene Protects Cone Photoreceptors Against Oxidative Stress

Abstract: Our work highlights the duality of the Nxnl1 gene, which protects the cones by two distinct mechanisms. Antioxid. Redox Signal. 24, 909-923.

Cited by 43 publications

References 37 publications

Coordinated Intervention of Microglial and Müller Cells in Light-Induced Retinal Degeneration

Coordinated Intervention of Microglial and Müller Cells in Light-Induced Retinal Degeneration

Metipranolol promotes structure and function of retinal photoreceptors in the rd10 mouse model of human retinitis pigmentosa

Taurine Depletion Causes ipRGC Loss and Increases Light-Induced Photoreceptor Degeneration

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