Downregulation of Cone-Specific Gene Expression and Degeneration of Cone Photoreceptors in the<i>Rpe65</i><sup>−/−</sup>Mouse at Early Ages

Znoiko, Sergey L.; Rohrer, Bäerbel; Lu, Kangmo; Lohr, Heather R.; Crouch, Rosalie K.; Xing, Jian

doi:10.1167/iovs.04-0653

Cited by 136 publications

(147 citation statements)

References 24 publications

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“…This inhibition may result in a deficient supply of 11-cis retinal chromophore, particularly for the macula which has higher demand for chromophore recycling. Lack of chromophore could destabilize opsin protein and subsequently lead to photoreceptor degeneration (41). The data presented here clearly demonstrate that micromolar concentrations of A2E inhibited isomerization/ hydrolysis of all-trans retinyl esters to 11-cis retinol catalyzed by RPE65, but did not affect the retinyl ester synthesis by LRAT.…”

Section: Discussionmentioning

confidence: 63%

Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt disease

Moiseyev

Nikolaeva

Chen

et al. 2010

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

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Stargardt disease (STGD) is the major form of inherited juvenile macular degeneration. Pyridinium bis-retinoid A2E is a major component of lipofuscin which accumulates in retinal pigment epithelium (RPE) cells in STGD and contributes to the disease pathogenesis. However, the precise role of A2E in vision loss is unclear. Here we report that A2E efficiently inhibits RPE65 isomerohydrolase, a key enzyme in the visual cycle. Subretinal injection of A2E significantly inhibited retinoid isomerohydrolase activity in mice. Likewise, A2E also inhibited isomerohydrolase activity in cells coexpressing RPE65, lecithin retinol acyltransferase (LRAT), and cellular retinaldehyde-binding protein. In vitro isomerohydrolase activity assays confirmed that A2E inhibited enzymatic activity of recombinant RPE65 in a concentration-dependent manner, but did not inhibit LRAT activity. The inhibition type for isomerohydrolase was found to be reversible and competitive with K i ¼ 13.6 μM. To determine the direct interaction of A2E with RPE65 protein, fluorescence binding assays were performed. As shown by fluorimetric titration, binding of purified RPE65 with A2E enhanced the bis-retinoid fluorescence. Consistently, the fluorescence of RPE65 decreased upon incubation with A2E. Both of these experiments suggest a direct, specific binding of A2E to RPE65. The binding constant for A2E and purified RPE65 was calculated to be 250 nM. These results demonstrate that A2E inhibits the regeneration of 11-cis retinal, the chromophore of visual pigments, which represents a unique mechanism by which A2E may impair vision in STGD.

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Section: Discussionmentioning

confidence: 63%

Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt disease

Moiseyev

Nikolaeva

Chen

et al. 2010

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

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“…Rpe65 −/− , a severe cone degeneration model, displays rapid ventral and central cone loss, whereas dorsal cones are preserved relatively well (20,21). Our cone density evaluation by peanut agglutinin (PNA) and cone arrestin (CAR) labeling in Rpe65 −/− mice showed a degeneration pattern similar to that reported previously (20,25), i.e., the ventral and central retina shows early onset, fast cone degeneration (about 10% of the wild-type level remained at postnatal day 30, P30), whereas the peripheral dorsal retina degenerated more slowly (about 50% of the wild-type level remained at P30) ( Fig. 1 A and B).…”

Section: Resultsmentioning

confidence: 99%

“…To determine whether TH signaling affects cone viability in inherited retinal degeneration, we investigated cone death/survival in retinal degeneration mouse models following TH signaling suppression and stimulation. Retinol isomerase RPE65-deficient (Rpe65 −/− ) (a model of Leber congenital amaurosis, LCA) (20,21) and cone photoreceptor function loss type 1 (cpfl1) mice (PDE6C mutation, a model of achromatopsia) (22), displaying fast and severe cone degeneration, were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone degeneration. Cone cyclic nucleotide-gated channel B subunit-deficient (Cngb3 −/− ) (a model of achromatopsia) (23) and guanylate cyclase 2e-deficient (Gucy2e −/− ) (another model of LCA) mice (24), displaying relatively slow progressive and moderate cone degeneration, were used to determine whether stimulating TH signaling (with T3…”

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confidence: 99%

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Thapa

Morris

et al. 2014

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

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Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models. Retinol isomerase RPE65-deficient mice [a model of Leber congenital amaurosis (LCA) with rapid cone loss] and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone death. Further, cone cyclic nucleotide-gated channel B subunitdeficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient mice (LCA with slower cone loss) were used to determine whether triiodothyronine (T3) treatment (stimulating TH signaling) causes deterioration of cones. We found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function loss type 1 mice increased about sixfold following antithyroid treatment. Cone density in cone cyclic nucleotidegated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about 40% following T3 treatment. The effect of TH signaling on cone viability appears to be independent of its regulation on cone opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective of cones, providing insights into cone preservation and therapeutic interventions.R od and cone photoreceptors degenerate under a variety of pathological conditions, including a wide array of hereditary retinal diseases, such as retinitis pigmentosa, macular degeneration, and cone-rod dystrophies. Defects in a large number of genes are linked to inherited retinal degenerative disorders (www.sph. uth.tmc.edu/RetNet/disease.htm), including those encoding enzymes involved in the recycling of 11-cis retinal in the retinal pigment epithelium (RPE), retinoid isomerase (RPE65), and lecithin retinol acyltransferase (LRAT), and the phototransductionassociated proteins (opsins, subunits of transducin, cGMP phosphodiesterase PDE6, guanylate cyclase, and cyclic nucleotidegated channel). There are currently no treatments for human retinal dystrophies. Despite a high genetic heterogeneity, the degenerating photoreceptors show common cellular disorder features, including oxidative damage (1, 2), endoplasmic reticulum stress (3, 4), and apoptosis (5, 6).Thyroid hormone (TH) signaling regulates cell proliferation, differentiation, and apoptosis. The role of TH signaling in retina regarding its regulation of cone opsin expression and patterning has been well documented (7,8). Most mammals possess dichromatic color vision that is mediated by two opsins with peak sensitivities to medium-long ...

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“…For example, there is no prescribed role for RPE65 in the retinoid cycle for cones in the cone dominated retina. However, knockout of this gene in the rod dominated retina of the mouse causes complete loss of cone function (Znoiko, Rohrer, Lu, Lohr, Crouch and Ma, 2005). Furthermore, it has also been shown that knocking out RPE65 in the 'all cone' Nrl −/− retina and in the 'cone only' retina of the Rho −/− mouse, causes cones to be functionless (Seeliger, Grimm, Stahlberg, Friedburg, Jaissle, Zrenner, Guo, Reme, Humphries, Hofmann, Biel, Fariss, Redmond and Wenzel, 2001;Wenzel, von, Oberhauser, Tanimoto, Grimm and Seeliger, 2007).…”

Section: Introductionmentioning

confidence: 99%

Retinoid processing in cone and Müller cell lines

Kanan

Kasus‐Jacobi

Moiseyev

et al. 2008

Experimental Eye Research

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To determine whether cones and Müller cells in the rod dominated retina, cooperate to regenerate the 11-cis retinal chromophore via the retinoid cycle, two cell lines from the rod dominated retinas of Murine were used for this study, 661W a mouse cell line derived from cones and rMC-1, a rat Müller cell line. Retinoid cycle enzymes were analyzed by RT-PCR and their catalytic activity were detected by incubation with retinoids and analyzed by HPLC. We found that, 661W cells are capable of reducing all-trans retinal to all-trans retinol due to the presence of multiple dehydrogenases and generate minor amounts of retinyl-ester. The rMC-1 cells take up all-trans retinol and oxidizes it to all-trans retinal or esterify it to retinyl-ester, but are incapable of isomerizing all-trans retinoids to 11-cis retinoids. This could be a reflection of lack of necessary activities in Müller cells in vivo which suggests that Müller cells do not contribute to retinoid cycling by regenerating 11-cis retinoids. Alternatively, this could be due to the potential that rMC-1, as a transformed cell line, has stopped expressing the proteins needed for the regeneration of 11-cis retinoids.

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Downregulation of Cone-Specific Gene Expression and Degeneration of Cone Photoreceptors in theRpe65^−/−Mouse at Early Ages

Cited by 136 publications

References 24 publications

Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt disease

Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt disease

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Retinoid processing in cone and Müller cell lines

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Downregulation of Cone-Specific Gene Expression and Degeneration of Cone Photoreceptors in theRpe65−/−Mouse at Early Ages

Cited by 136 publications

References 24 publications

Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt disease

Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt disease

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

Retinoid processing in cone and Müller cell lines

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Downregulation of Cone-Specific Gene Expression and Degeneration of Cone Photoreceptors in theRpe65^−/−Mouse at Early Ages