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Krzysztof Palczewski – One of the best experts on this subject based on the ideXlab platform.

  • Conditional Ablation of Retinol Dehydrogenase 10 in the Retinal Pigmented Epithelium Causes Delayed Dark Adaption in Mice
    Journal of Biological Chemistry, 2015
    Co-Authors: Bhubanananda Sahu, Krzysztof Palczewski, Wenyu Sun, Lindsay Perusek, Vipulkumar Parmar, Michael D. Griswold, Akiko Maeda


    Regeneration of the visual chromophore, 11-Cis-Retinal, is a crucial step in the visual cycle required to sustain vision. This cycle consists of sequential biochemical reactions that occur in photoreceptor cells and the retinal pigmented epithelium (RPE). Oxidation of 11-cis-retinol to 11-Cis-Retinal is accomplished by a family of enzymes termed 11-cis-retinol dehydrogenases, including RDH5 and RDH11. Double deletion of Rdh5 and Rdh11 does not limit the production of 11-Cis-Retinal in mice. Here we describe a third retinol dehydrogenase in the RPE, RDH10, which can produce 11-Cis-Retinal. Mice with a conditional knock-out of Rdh10 in RPE cells (Rdh10 cKO) displayed delayed 11-Cis-Retinal regeneration and dark adaption after bright light illumination. Retinal function measured by electroretinogram after light exposure was also delayed in Rdh10 cKO mice as compared with controls. Double deletion of Rdh5 and Rdh10 (cDKO) in mice caused elevated 11/13-cis-retinyl ester content also seen in Rdh5(-/-)Rdh11(-/-) mice as compared with Rdh5(-/-) mice. Normal retinal morphology was observed in 6-month-old Rdh10 cKO and cDKO mice, suggesting that loss of Rdh10 in the RPE does not negatively affect the health of the retina. Compensatory expression of other retinol dehydrogenases was observed in both Rdh5(-/-) and Rdh10 cKO mice. These results indicate that RDH10 acts in cooperation with other RDH isoforms to produce the 11-Cis-Retinal chromophore needed for vision.

  • Cellular Retinaldehyde Binding Protein—Different Binding Modes and Micro-Solvation Patterns for High-Affinity 9-cis- and 11-Cis-Retinal Substrates
    The Journal of Physical Chemistry B, 2013
    Co-Authors: Rachel E. Helbling, Marcin Golczak, Krzysztof Palczewski, Christin S. Bolze, Achim Stocker, Michele Cascella


    We use molecular dynamics (MD) simulations to determine the binding properties of different retinoid species to cellular retinaldehyde binding protein (CRALBP). The complexes formed by 9-cis-retinal or 11-Cis-Retinal bound to both the native protein and the R234W mutant, associated to Bothnia-retina dystrophy, are investigated. The presented studies are also complemented by analysis of the binding structures of the CRALBP/9-cis-retinol and CRALBP/9,13- dicis-retinal complexes. We find that the poor X-ray scattering properties of the polyene tail of the ligand in all wild-type complexes can be attributed to a high mobility of this region, which does not localize in a single binding conformation even at very low temperatures. Our simulations report a clear difference in the residual solvation pattern in CRALBP complexes with either 9-cis- or 9,13-dicis-retinal. The reported structures indicate that the microsolvation properties of the ligand are the key structural element triggering the very recently discovered isomerase activity of this protein. The binding geometries obtained by MD simulations are validated by calculation of the respective optical spectra by the ZINDO/S semiempirical method, which can reproduce with good qualitative agreement the different red-shifts of the first absorption band of the different complexes.

  • limited roles of rdh8 rdh12 and abca4 in all trans retinal clearance in mouse retina
    Investigative Ophthalmology & Visual Science, 2009
    Co-Authors: Akiko Maeda, Marcin Golczak, Tadao Maeda, Krzysztof Palczewski


    A major intermediate of the retinoid (visual) cycle, the ocular vitamin A recycling system required for vision, is all-trans-retinal.1 Regeneration of the chromophore, 11-Cis-Retinal, is essential for continuous renewal of light-sensitive visual pigments in the vertebrate retina. Whereas inadequate 11-Cis-Retinal production leads to congenital blindness in humans, accumulation of the photoisomerized chromophore all-trans-retinal also can be detrimental. Such is the case when this reactive aldehyde is not efficiently cleared from the internal membranes of retinal outer segment discs.2,3 Clearance of all-trans-retinal consists of two steps: (1) translocation of all-trans-retinal across the photoreceptor disc membranes by ATP-binding cassette transporter 4 (ABCA4), and (2) reduction of all-trans-retinal to all-trans-retinol by retinol dehydrogenase 8 (RDH8) expressed in the outer segments of photoreceptors and RDH12 located in photoreceptor inner segments.4–6

    In humans, lipofuscin fluorophores accumulate with age in the retinal pigmented epithelium (RPE), especially in RPE cells underlying the macula.7,8 Such accumulation has been considered to constitute one of the major risk factors for age-related macular degeneration (AMD), the predominant cause of legal blindness in developed countries.9 Lipofuscin fluorophores also are especially abundant in Stargardt disease, the most common juvenile form of macular degeneration.10 Di-retinoid-pyridinium-ethanolamine (A2E), the major fluorophore of lipofuscin, is formed by condensation of phosphatidylethanolamine with two molecules of all-trans-retinal followed by oxidation and hydrolysis of the phosphate ester.11 Various mechanisms have been proposed to explain the toxicity of A2E. These include properties of A2E as a cationic detergent,12 physiologic interference with RPE function,13,14 and radical reactions induced by light-dependent A2E oxidation.15

    Recently, we reported that genetic ablation of Rdh8 and Abca4, two important enzymes responsible for all-trans-retinal clearance from photoreceptors, caused severe retinal degeneration in mice.16 Even though this disease was associated with accumulation of all-trans-retinal condensation products such as A2E and all-trans-retinal dimer (RALdi), the mechanisms of RPE and photoreceptor death remain to be clarified. Although Rdh8 is the major dehydrogenase responsible for clearing all-trans-retinal from outer segments of photoreceptor cells,17 Rdh12 also contributes to this process in the inner segments of photoreceptor cells, and mutations in Rdh12 are associated with congenital blindness.18 Therefore, we used genetically engineered mice lacking Rdh8, Rdh12, and/or Abca4 alone or in various combinations together with cell culture experiments to investigate the roles of these enzymes in all-trans-retinal clearance and induction of progressive light-dependent severe retinal degeneration.

Gabriel H Travis – One of the best experts on this subject based on the ideXlab platform.

  • non photopic and photopic visual cycles differentially regulate immediate early and late phases of cone photoreceptor mediated vision
    bioRxiv, 2020
    Co-Authors: Rebecca Ward, Joanna J Kaylor, Diego Cobice, Dionissia A Pepe, Eoghan M Mcgarrigle, Susan E Brockerhoff, James B Hurley, Gabriel H Travis, Breandán N. Kennedy


    Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Muller glia. In the RPE, isomerization of all-trans-retinyl esters (atRE) to 11-cis-retinol (11cROL) is mediated by the retinoid isomerohydrolase Rpe65. An alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Muller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, whereas emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaption displayed significantly attenuated immediate photopic vision concomitantly with significantly reduced 11-Cis-Retinaldehyde (11cRAL). Following 30 minutes of light, early photopic vision recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde (9cRAL) supplementation. Genetic knockout of degs1 or retinaldehyde-binding protein 1b (rlbp1b) revealed that neither are required for photopic vision in zebrafish. Our findings define the molecular and temporal requirements of the non-photopic and photopic visual cycles for mediating vision in bright light.

  • light driven regeneration of cone visual pigments through a mechanism involving rgr opsin in muller glial cells
    Neuron, 2019
    Co-Authors: Ala Morshedian, Joanna J Kaylor, Roxana A Radu, Avian Tsan, Rikard Frederiksen, Lily Yuan, Alapakkam P Sampath, Gordon L Fain, Gabriel H Travis


    While rods in the mammalian retina regenerate rhodopsin through a well-characterized pathway in cells of the retinal pigment epithelium (RPE), cone visual pigments are thought to regenerate in part through an additional pathway in Muller cells of the neural retina. The proteins comprising this intrinsic retinal visual cycle are unknown. Here, we show that RGR opsin and retinol dehydrogenase-10 (Rdh10) convert all-trans-retinol to 11-cis-retinol during exposure to visible light. Isolated retinas from Rgr+/+ and Rgr-/- mice were exposed to continuous light, and cone photoresponses were recorded. Cones in Rgr-/- retinas lost sensitivity at a faster rate than cones in Rgr+/+ retinas. A similar effect was seen in Rgr+/+ retinas following treatment with the glial cell toxin, α-aminoadipic acid. These results show that RGR opsin is a critical component of the Muller cell visual cycle and that regeneration of cone visual pigment can be driven by light.

  • identification of des1 as a vitamin a isomerase in muller glial cells of the retina
    Nature Chemical Biology, 2013
    Co-Authors: Joanna J Kaylor, Quan Yuan, Jeremy D Cook, Shanta Sarfare, Jacob Makshanoff, Samer Habib, Nathaniel C Roybal, Tongzhou Xu, Steven Nusinowitz, Gabriel H Travis


    Equilibrium isomerization of retinol is a new activity now attributable to DES1. 11-cis-retinol synthesized by DES1 in Muller cells of the retina can be converted to the visual chromophore for regenerating opsin pigment in cone photoreceptors.

Yiannis Koutalos – One of the best experts on this subject based on the ideXlab platform.

  • Interphotoreceptor retinoid-binding protein removes all-trans-retinol and retinal from rod outer segments, preventing lipofuscin precursor formation.
    Journal of Biological Chemistry, 2017
    Co-Authors: Chunhe Chen, Leopold Adler, Patrice Goletz, Federico Gonzalez-fernandez, Debra A. Thompson, Yiannis Koutalos


    : Interphotoreceptor retinoid-binding protein (IRBP) is a specialized lipophilic carrier that binds the all-trans and 11-cis isomers of retinal and retinol, and this facilitates their transport between photoreceptors and cells in the retina. One of these retinoids, all-trans-retinal, is released in the rod outer segment by photoactivated rhodopsin after light excitation. Following its release, all-trans-retinal is reduced by the retinol dehydrogenase RDH8 to all-trans-retinol in an NADPH-dependent reaction. However, all-trans-retinal can also react with outer segment components, sometimes forming lipofuscin precursors, which after conversion to lipofuscin accumulate in the lysosomes of the retinal pigment epithelium and display cytotoxic effects. Here, we have imaged the fluorescence of all-trans-retinol, all-trans-retinal, and lipofuscin precursors in real time in single isolated mouse rod photoreceptors. We found that IRBP removes all-trans-retinol from individual rod photoreceptors in a concentration-dependent manner. The rate constant for retinol removal increased linearly with IRBP concentration with a slope of 0.012 min-1 μm-1 IRBP also removed all-trans-retinal, but with much less efficacy, indicating that the reduction of retinal to retinol promotes faster clearance of the photoisomerized rhodopsin chromophore. The presence of physiological IRBP concentrations in the extracellular medium resulted in lower levels of all-trans-retinal and retinol in rod outer segments following light exposure. It also prevented light-induced lipofuscin precursor formation, but it did not remove precursors that were already present. These findings reveal an important and previously unappreciated role of IRBP in protecting the photoreceptor cells against the cytotoxic effects of accumulated all-trans-retinal.

  • RPE65 and the Accumulation of Retinyl Esters in Mouse Retinal Pigment Epithelium
    Photochemistry and Photobiology, 2017
    Co-Authors: Colleen Sheridan, Nicholas P. Boyer, Rosalie K. Crouch, Yiannis Koutalos


    The RPE65 protein of the retinal pigment epithelium (RPE) enables the conversion of retinyl esters to the visual pigment chromophore 11-cis retinal. Fresh 11-cis retinal is generated from retinyl esters following photoisomerization of the visual pigment chromophore to all-trans during light detection. Large amounts of esters accumulate in Rpe65-/- mice, indicating their continuous formation when 11-cis retinal generation is blocked. We hypothesized that absence of light, by limiting the conversion of esters to 11-cis retinal, would also result in the build-up of retinyl esters in the RPE of wild-type mice. We used HPLC to quantify ester levels in organic extracts of the RPE from wild-type and Rpe65-/- mice. Retinyl ester levels in Sv/129 wild-type mice that were dark adapted for various intervals over a 4-week period were similar to those in mice raised in cyclic light. In C57BL/6 mice however, which contain less Rpe65 protein, dark adaptation was accompanied by an increase in ester levels compared to cyclic light controls. Retinyl ester levels were much higher in Rpe65-/- mice compared to wild type and kept increasing with age. The results suggest that the RPE65 role in retinyl ester homeostasis extends beyond enabling the formation of 11-cis retinal.

  • The 11-cis Retinal Origins of Lipofuscin in the Retina.
    Progress in Molecular Biology and Translational Science, 2015
    Co-Authors: Leopold Adler, Chunhe Chen, Rosalie K. Crouch, Nicholas P. Boyer, Zsolt Ablonczy, Yiannis Koutalos


    Lipofuscin is a fluorescent mixture of partially digested proteins and lipids that accumulates with age in the lysosomal compartment of the retinal pigment epithelium (RPE) of the eye. Because it has been found to have significant cytotoxic potential, lipofuscin is thought to play a role in retinal degeneration diseases including age-related macular degeneration and Stargardt disease, a form of juvenile macular degeneration. The only known components of lipofuscin are bis-retinoids, the condensation products of two molecules of retinal. The bulk of lipofuscin is thought to originate in the rod photoreceptor outer segments as a by-product of reactions involving the retinal chromophore of rhodopsin. 11-cis retinal flows from the RPE into the rod outer segments, where it combines with opsin to form rhodopsin; all-trans retinal is released into the rod outer segments by photoactivated rhodopsin following its excitation by light. Both 11-cis and all-trans retinal can generate lipofuscin-like fluorophores and bis-retinoids when added to rod outer segment membranes. The levels of lipofuscin precursor fluorophores present in the outer segments of dark-adapted rods are similar in cyclic-light- and dark-reared mice, as are the levels of accumulated lipofuscin in the RPE. Because the retinol dehydrogenase enzyme present in rod outer segments can reduce all-trans but not 11-cis retinal, lipofuscin precursors are more likely to form from 11-cis than all-trans retinal, even under cyclic light conditions. Thus, 11-cis retinal may be the primary source of lipofuscin in the retina.