Photoreceptor Death, Trophic Factor Expression, Retinal Oxygen Status, and Photoreceptor Function in the P23H Rat

Yu, Dao‐Yi; Cringle, Stephen J.; Valter, Krisztina; Walsh, Natalie; Lee, Donald; Stone, Jonathan

doi:10.1167/iovs.03-0845

Cited by 149 publications

(145 citation statements)

References 22 publications

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“…Rods are more numerous than cones and are metabolically active cells with a high level of oxygen consumption. Choroidal vessels are not subject to autoregulation by tissue oxygen levels and as death of rods occurs, the level of oxygen in the retina increases (5,6). It has been postulated that the narrowing of retinal vessels, one of the characteristic features of the RP phenotype, is due to high levels of oxygen in the retina (7), because retinal vessels are capable of autoregulation and constrict when tissue levels of oxygen are high.…”

mentioning

confidence: 99%

Antioxidants reduce cone cell death in a model of retinitis pigmentosa

Komeima

Rogers

Lü³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

365

364

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Retinitis pigmentosa (RP) is a label for a group of diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cones. The mechanism of cone cell death is uncertain. Rods are a major source of oxygen utilization in the retina and, after rods die, the level of oxygen in the outer retina is increased. In this study, we used the rd1 mouse model of RP to test the hypothesis that cones die from oxidative damage. A mixture of antioxidants was selected to try to maximize protection against oxidative damage achievable by exogenous supplements; ␣-tocopherol (200 mg͞kg), ascorbic acid (250 mg͞kg), Mn(III)tetrakis (4-benzoic acid) porphyrin (10 mg͞kg), and ␣-lipoic acid (100 mg͞kg). Mice were treated with daily injections of the mixture or each component alone between postnatal day (P)18 and P35. Between P18 and P35, there was an increase in two biomarkers of oxidative damage, carbonyl adducts measured by ELISA and immunohistochemical staining for acrolein, in the retinas of rd1 mice. The staining for acrolein in remaining cones at P35 was eliminated in antioxidant-treated rd1 mice, confirming that the treatment markedly reduced oxidative damage in cones; this was accompanied by a 2-fold increase in cone cell density and a 50% increase in medium-wavelength cone opsin mRNA. Antioxidants also caused some preservation of cone function based upon photopic electroretinograms. These data support the hypothesis that gradual cone cell death after rod cell death in RP is due to oxidative damage, and that antioxidant therapy may provide benefit. oxidative damage ͉ photoreceptors ͉ retinal degenerations R etinitis pigmentosa (RP) refers to a group of diseases in which a mutation results in death of rod photoreceptors followed by gradual death of cones. The diseases referred to as RP show a similar phenotype consisting of pigmented spots scattered throughout the retina, narrowed retinal vessels, and retinal sheen suggesting atrophy. At one time, it was felt that inflammation was important in the pathogenesis, and hence the term ''retinitis'' was paired with a descriptor for the most prominent feature of the phenotype, the scattered pigment, resulting in the term retinitis pigmentosa. It is now known that this phenotype results whenever there is widespread rod photoreceptor cell death. Although toxins or infections can occasionally cause widespread rod death, it occurs most commonly when there is a mutation in a gene that is selectively expressed in rods and, either through gain or loss of function, the mutation promotes rod cell death. Mutations in 36 different genes have been found to cause RP, and mutations in many more cause widespread rod cell death in association with syndromes that have extraocular manifestations (www.sph.uth.tmc.edu͞RetNet͞ sum-dis.htm).How does diffuse death of rods throughout the retina result in the distinctive phenotype that ophthalmologists recognize as RP? Rods have an intimate relationship, both structurally and functionally, with retinal pigmen...

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mentioning

confidence: 99%

Antioxidants reduce cone cell death in a model of retinitis pigmentosa

Komeima

Rogers

Lü³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

365

364

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“…Recent evidence has implicated oxidative damage as a contributor to death of cones in retinitis pigmentosa and to death of both photoreceptor cell types in age-related macular degeneration (5). After rods die, oxygen consumption in the outer retina is markedly reduced, and tissue oxygen levels become substantially elevated (6). This results in progressive oxidative damage to cones and gradual cone cell death, which can be slowed by antioxidants (7).…”

mentioning

confidence: 99%

The Thioredoxin-like Protein Rod-derived Cone Viability Factor (RdCVFL) Interacts with TAU and Inhibits Its Phosphorylation in the Retina

Fridlich

Delalande

Jaillard

et al. 2009

Molecular & Cellular Proteomics

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Rod-derived cone viability factor (RdCVF) is produced by the Nxnl1 gene that codes for a second polypeptide, RdCVFL, by alternative splicing. Although the role of RdCVF in promoting cone survival has been described, the implication of RdCVFL, a putative thioredoxin enzyme, in the protection of photoreceptors is presently unknown. Using a proteomics approach we identified 90 proteins interacting with RdCVFL including the microtubule-binding protein TAU. We demonstrate that the level of phosphorylation of TAU is increased in the retina of the Nxnl1 ؊/؊ mice as it is hyperphosphorylated in the brain of patients suffering from Alzheimer disease, presumably in some cases through oxidative stress. Using a cell-based assay, we show that RdCVFL inhibits TAU phosphorylation. In vitro, RdCVFL protects TAU from oxidative damage. Photooxidative stress is implicated in retinal degeneration, particularly in retinitis pigmentosa, where it is considered to be a contributor to secondary cone death. The functional interaction between RdCVFL and TAU described here is the first characterization of the RdCVFL signaling pathway involved in neuronal cell death mediated by oxidative stress.

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“…However, cone death often does not occur until many months after rod death (Carter-Dawson et al, 1978;Milam et al, 1998;Berson, 2008;Lin et al, 2009;Punzo et al, 2009). Another model holds that there is an increase in oxidative damage to cones once the rods have died (Yu et al, 2004;Shen et al, 2005;Komeima et al, 2006). This model also suggests a therapy, that is, delivery of antioxidants or genes encoding antioxidation enzymes.…”

Section: Overview Of Therapeutic Approaches To Rpmentioning

confidence: 99%

“…As mentioned above, oxidative stress has been suggested as one of the causes of cone dysfunction and death in RP (Yu et al, 2004;Shen et al, 2005;Komeima et al, 2006). As the rods die in RP, the flow of oxygen from the choroidal circulation does not abate, and thus each cone is exposed to increasing amounts of oxygen (Yu et al, 2000(Yu et al, , 2004.…”

Section: Treatment With Antioxidantsmentioning

confidence: 99%

Emerging Gene Therapies for Retinal Degenerations

Cepko¹

2012

J. Neurosci.

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Photoreceptor Death, Trophic Factor Expression, Retinal Oxygen Status, and Photoreceptor Function in the P23H Rat

Cited by 149 publications

References 22 publications

Antioxidants reduce cone cell death in a model of retinitis pigmentosa

Antioxidants reduce cone cell death in a model of retinitis pigmentosa

The Thioredoxin-like Protein Rod-derived Cone Viability Factor (RdCVFL) Interacts with TAU and Inhibits Its Phosphorylation in the Retina

Emerging Gene Therapies for Retinal Degenerations

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