The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Charlotte E Reme - One of the best experts on this subject based on the ideXlab platform.
-
rpe65 as a modifier gene for inherited retinal degeneration
European Journal of Neuroscience, 2006Co-Authors: Marijana Samardzija, Andreas Wenzel, M Naash, Charlotte E Reme, Christian GrimmAbstract:Light accelerates progression of retinal degeneration in many animal models of retinitis pigmentosa (RP). A sequence variant in the Rpe65 gene (Rpe65450Leu or Rpe65450Met) can act as a modulator of Light-Damage susceptibility in mice by influencing the kinetics of rhodopsin regeneration and thus by modulating the photon absorption. Depending on exposure duration and Light intensity applied, white fluorescent Light induces photoreceptor apoptosis and retinal degeneration in wild-type mice by the activation of one of two known molecular pathways. These pathways depend, respectively, on activation of the transcription factor c-Fos/AP-1 and on phototransduction activity. Here we tested Rpe65 as a genetic modifier for inherited retinal degeneration and analysed which degenerative pathway is activated in a transgenic mouse model of autosomal dominant RP. We show that retinal degeneration was reduced in mice expressing the Rpe65450Met variant and that these mice retained more visual pigment rhodopsin than did transgenic mice expressing the Rpe65450Leu variant. In addition, lack of phototransduction slowed retinal degeneration whereas ablation of c-Fos had no effect. We conclude that sequence variations in the Rpe65 gene can act as genetic modifiers in inherited retinal degeneration, presumably by regulating the daily rate of photon absorption through the modulation of rhodopsin regeneration kinetics. Increased absorption of photons and/or Light sensitivity appear to accelerate retinal degeneration via an apoptotic cascade which involves phototransduction but not c-Fos.
-
molecular mechanisms of Light induced photoreceptor apoptosis and neuroprotection for retinal degeneration
Progress in Retinal and Eye Research, 2005Co-Authors: Andreas Wenzel, Marijana Samardzija, Christian Grimm, Charlotte E RemeAbstract:Human retinal dystrophies and degenerations and Light-induced retinal degenerations in animal models are sharing an important feature: visual cell death by apoptosis. Studying apoptosis may thus provide an important handle to understand mechanisms of cell death and to develop potential rescue strategies for blinding retinal diseases. Apoptosis is the regulated elimination of individual cells and constitutes an almost universal principle in developmental histogenesis and organogenesis and in the maintenance of tissue homeostasis in mature organs. Here we present an overview on molecular and cellular mechanisms of apoptosis and summarize recent developments. The classical concept of apoptosis being initiated and executed by endopeptidases that cleave proteins at aspartate residues (Caspases) can no longer be held in its strict sense. There is an increasing number of caspase-independent pathways, involving apoptosis inducing factor, endonuclease G, poly-(ADP-ribose) polymerase-1, proteasomes, lysosomes and others. Similarly, a considerable number and diversity of pro-apoptotic stimuli is being explored. We focus on apoptosis pathways in our model: Light-Damage induced by short exposures to bright white Light and highLight those essential conditions known so far in the apoptotic death cascade. In our model, the visual pigment rhodopsin is the essential mediator of the initial death signal. The rate of rhodopsin regeneration defines Damage threshold in different strains of mice. This rate depends on the level of the pigment epithelial protein RPE65, which in turn depends on the amino acid (leucine or methionine) encoded at position 450. Activation of the pro-apoptotic transcription factor AP-1 constitutes an essential death signal. Inhibition of rhodopsin regeneration as well as suppression of AP-1 confers complete protection in our system. Furthermore, we describe observations in other Light-Damage systems as well as characteristics of animal models for RP with particular emphasis on rescue strategies. There is a vast array of different neuroprotective cytokines that are applied in Light-Damage and RP animal models and show diverging efficacy. Some cytokines protect against Light Damage as well as against RP in animal models. At present, the mechanisms of neuroprotective/anti-apoptotic action represent a "black box" which needs to be explored. Even though acute Light Damage and RP animal models show different characteristics in many respects, we hope to gain insights into apoptotic mechanisms for both conditions by studying Light Damage and comparing results with those obtained in animal models. In our view, future directions may include the investigation of different apoptotic pathways in Light Damage (and inherited animal models). Emphasis should also be placed on mechanisms of removal of dead cells in apoptosis, which appears to be more important than initially recognized. In this context, a stimulating concept concerns age-related macular degeneration, where an insufficiency of macrophages removing debris that results from cell death and photoreceptor turnover might be an important pathogenetic event. In acute Light Damage, the appearance of macrophages as well as phagocytosis by the retinal pigment epithelium are a consistent and conspicuous feature, which lends itself to the study of removal of cellular debris in apoptosis. We are aware of the many excellent reviews and the earlier work paving the way to our current knowledge and understanding of retinal degeneration, photoreceptor apoptosis and neuroprotection. However, we limited this review mainly to work published in the last 7-8 years and we apologize to all the researchers which have contributed to the field but are not cited here.
-
rhodopsin mediated blue Light Damage to the rat retina effect of photoreversal of bleaching
Investigative Ophthalmology & Visual Science, 2001Co-Authors: Christian Grimm, Andreas Wenzel, Farhad Hafezi, Theodore P Williams, Pascal Rol, Charlotte E RemeAbstract:METHODS. Eyes of anesthetized rats and mice that did or did not contain rhodopsin were exposed to green (550 6 10 nm) or deep blue (403 6 10 nm) Light for up to 2 hours. Rats with nearly rhodopsinless retinas were obtained by bleaching rhodopsin in animals with inhibited metabolic rhodopsin regeneration—that is, under halothane anesthesia. In addition, Rpe65 2/2 mice that are completely without rhodopsin were used to test the susceptibility to blue-Light Damage of a rodent retina completely devoid of the visual pigment. Effects of illumination on photoreceptor morphology were assessed 24 hours or 10 days thereafter by morphologic and biochemical methods. RESULTS. Exposure to blue Light resulted in severe retinal Damage and activation of the transcription factor AP-1 in rats. In contrast, green Light had no effect. When rhodopsin was almost completely bleached by short-term green-Light exposure while metabolic regeneration (but not photoreversal) was prevented by halothane anesthesia, blue-Light exposure induced distinct lesions in rat retinas. When both metabolic rhodopsin regeneration and photoreversal of bleaching were almost completely inhibited, blue-Light exposure caused only very moderate lesions. When mice without rhodopsin were exposed to blue Light, no Damage occurred, in contrast to wild-type control mice. CONCLUSIONS. Short time exposure to blue Light has deleterious effects on retinal morphology. Because Damage was observed only in the presence of the visual pigment, blue-Light‐induced retinal degeneration is rhodopsin mediated. Absorption of blue
-
the rpe65 leu450met variation increases retinal resistance against Light induced degeneration by slowing rhodopsin regeneration
The Journal of Neuroscience, 2001Co-Authors: Andreas Wenzel, Charlotte E Reme, Farhad Hafezi, Theodore P Williams, Christian GrimmAbstract:Excessive Light can cause retinal degeneration and may be an environmental cofactor accelerating retinal dystrophies and age-related diseases. In rodent models, the Light Damage susceptibility (LDS) of the retina is determined genetically. In two mouse strains, with different degrees of LDS, a Leu450Met variation in the pigment epithelial protein RPE65 was shown recently to cosegregate with low LDS. Because Light Damage is rhodopsin-mediated, and RPE65 is essential for the regeneration of rhodopsin in the visual cycle, we analyzed this variation regarding rhodopsin metabolism and LDS in four mouse strains. We found that, in contrast to previous assertions, LDS does not correlate with the maximal retinal content of rhodopsin present after dark adaptation. Instead, LDS correlated positively with the kinetics of rhodopsin regeneration, which determine rhodopsin availability during Light exposure. Light Damage occurred after absorption of a threshold dose of photons and thus fast regeneration, as observed in those two strains having Leu at position 450 of RPE65, was correlated with the occurrence of photoreceptor apoptosis after short exposure. In contrast, mice with the Leu450Met variation of Rpe65 regenerated rhodopsin with slow kinetics and showed an increased resistance to Light-induced retinal degeneration. In these mice, RPE65 protein levels were reduced by a post-transcriptional mechanism. F 1 hybrid mice, carrying one normal and one variant Rpe65 gene, had intermediate levels of the corresponding protein and showed intermediate rhodopsin regeneration kinetics and an intermediate LDS. Thus, none of the two variants of Rpe65 had a dominant effect.
-
protection of rpe65 deficient mice identifies rhodopsin as a mediator of Light induced retinal degeneration
Nature Genetics, 2000Co-Authors: Christian Grimm, Andreas Wenzel, Farhad Hafezi, Shirley Yu, T M Redmond, Charlotte E RemeAbstract:Light-induced apoptosis of photoreceptors represents an animal model for retinal degeneration1. Major human diseases that affect vision, such as age-related macular degeneration (AMD) and some forms of retinitis pigmentosa (RP), may be promoted by Light2,3,4,5,6,7. The receptor mediating Light Damage, however, has not yet been conclusively identified; candidate molecules include prostaglandin synthase8, cytochrome oxidase9, rhodopsin10, and opsins of the cones and the retinal pigment epithelium11 (PE). We exposed to bright Light two groups of genetically altered mice that lack the visual pigment rhodopsin (Rpe65−/− and Rho−/−). The gene Rpe65 is specifically expressed in the PE and essential for the re-isomerization of all-trans retinol in the visual cycle and thus for the regeneration of rhodopsin after bleaching12. Rho−/− mice do not express the apoprotein opsin in photoreceptors, which, consequently, do not contain rhodopsin13. We show that photoreceptors lacking rhodopsin in these mice are completely protected against Light-induced apoptosis. The transcription factor AP-1, a central element in the apoptotic response to Light14,15, is not activated in the absence of rhodopsin, indicating that rhodopsin is essential for the generation or transduction of the intracellular death signal induced by Light.
Christian Grimm - One of the best experts on this subject based on the ideXlab platform.
-
rpe65 as a modifier gene for inherited retinal degeneration
European Journal of Neuroscience, 2006Co-Authors: Marijana Samardzija, Andreas Wenzel, M Naash, Charlotte E Reme, Christian GrimmAbstract:Light accelerates progression of retinal degeneration in many animal models of retinitis pigmentosa (RP). A sequence variant in the Rpe65 gene (Rpe65450Leu or Rpe65450Met) can act as a modulator of Light-Damage susceptibility in mice by influencing the kinetics of rhodopsin regeneration and thus by modulating the photon absorption. Depending on exposure duration and Light intensity applied, white fluorescent Light induces photoreceptor apoptosis and retinal degeneration in wild-type mice by the activation of one of two known molecular pathways. These pathways depend, respectively, on activation of the transcription factor c-Fos/AP-1 and on phototransduction activity. Here we tested Rpe65 as a genetic modifier for inherited retinal degeneration and analysed which degenerative pathway is activated in a transgenic mouse model of autosomal dominant RP. We show that retinal degeneration was reduced in mice expressing the Rpe65450Met variant and that these mice retained more visual pigment rhodopsin than did transgenic mice expressing the Rpe65450Leu variant. In addition, lack of phototransduction slowed retinal degeneration whereas ablation of c-Fos had no effect. We conclude that sequence variations in the Rpe65 gene can act as genetic modifiers in inherited retinal degeneration, presumably by regulating the daily rate of photon absorption through the modulation of rhodopsin regeneration kinetics. Increased absorption of photons and/or Light sensitivity appear to accelerate retinal degeneration via an apoptotic cascade which involves phototransduction but not c-Fos.
-
molecular mechanisms of Light induced photoreceptor apoptosis and neuroprotection for retinal degeneration
Progress in Retinal and Eye Research, 2005Co-Authors: Andreas Wenzel, Marijana Samardzija, Christian Grimm, Charlotte E RemeAbstract:Human retinal dystrophies and degenerations and Light-induced retinal degenerations in animal models are sharing an important feature: visual cell death by apoptosis. Studying apoptosis may thus provide an important handle to understand mechanisms of cell death and to develop potential rescue strategies for blinding retinal diseases. Apoptosis is the regulated elimination of individual cells and constitutes an almost universal principle in developmental histogenesis and organogenesis and in the maintenance of tissue homeostasis in mature organs. Here we present an overview on molecular and cellular mechanisms of apoptosis and summarize recent developments. The classical concept of apoptosis being initiated and executed by endopeptidases that cleave proteins at aspartate residues (Caspases) can no longer be held in its strict sense. There is an increasing number of caspase-independent pathways, involving apoptosis inducing factor, endonuclease G, poly-(ADP-ribose) polymerase-1, proteasomes, lysosomes and others. Similarly, a considerable number and diversity of pro-apoptotic stimuli is being explored. We focus on apoptosis pathways in our model: Light-Damage induced by short exposures to bright white Light and highLight those essential conditions known so far in the apoptotic death cascade. In our model, the visual pigment rhodopsin is the essential mediator of the initial death signal. The rate of rhodopsin regeneration defines Damage threshold in different strains of mice. This rate depends on the level of the pigment epithelial protein RPE65, which in turn depends on the amino acid (leucine or methionine) encoded at position 450. Activation of the pro-apoptotic transcription factor AP-1 constitutes an essential death signal. Inhibition of rhodopsin regeneration as well as suppression of AP-1 confers complete protection in our system. Furthermore, we describe observations in other Light-Damage systems as well as characteristics of animal models for RP with particular emphasis on rescue strategies. There is a vast array of different neuroprotective cytokines that are applied in Light-Damage and RP animal models and show diverging efficacy. Some cytokines protect against Light Damage as well as against RP in animal models. At present, the mechanisms of neuroprotective/anti-apoptotic action represent a "black box" which needs to be explored. Even though acute Light Damage and RP animal models show different characteristics in many respects, we hope to gain insights into apoptotic mechanisms for both conditions by studying Light Damage and comparing results with those obtained in animal models. In our view, future directions may include the investigation of different apoptotic pathways in Light Damage (and inherited animal models). Emphasis should also be placed on mechanisms of removal of dead cells in apoptosis, which appears to be more important than initially recognized. In this context, a stimulating concept concerns age-related macular degeneration, where an insufficiency of macrophages removing debris that results from cell death and photoreceptor turnover might be an important pathogenetic event. In acute Light Damage, the appearance of macrophages as well as phagocytosis by the retinal pigment epithelium are a consistent and conspicuous feature, which lends itself to the study of removal of cellular debris in apoptosis. We are aware of the many excellent reviews and the earlier work paving the way to our current knowledge and understanding of retinal degeneration, photoreceptor apoptosis and neuroprotection. However, we limited this review mainly to work published in the last 7-8 years and we apologize to all the researchers which have contributed to the field but are not cited here.
-
rhodopsin mediated blue Light Damage to the rat retina effect of photoreversal of bleaching
Investigative Ophthalmology & Visual Science, 2001Co-Authors: Christian Grimm, Andreas Wenzel, Farhad Hafezi, Theodore P Williams, Pascal Rol, Charlotte E RemeAbstract:METHODS. Eyes of anesthetized rats and mice that did or did not contain rhodopsin were exposed to green (550 6 10 nm) or deep blue (403 6 10 nm) Light for up to 2 hours. Rats with nearly rhodopsinless retinas were obtained by bleaching rhodopsin in animals with inhibited metabolic rhodopsin regeneration—that is, under halothane anesthesia. In addition, Rpe65 2/2 mice that are completely without rhodopsin were used to test the susceptibility to blue-Light Damage of a rodent retina completely devoid of the visual pigment. Effects of illumination on photoreceptor morphology were assessed 24 hours or 10 days thereafter by morphologic and biochemical methods. RESULTS. Exposure to blue Light resulted in severe retinal Damage and activation of the transcription factor AP-1 in rats. In contrast, green Light had no effect. When rhodopsin was almost completely bleached by short-term green-Light exposure while metabolic regeneration (but not photoreversal) was prevented by halothane anesthesia, blue-Light exposure induced distinct lesions in rat retinas. When both metabolic rhodopsin regeneration and photoreversal of bleaching were almost completely inhibited, blue-Light exposure caused only very moderate lesions. When mice without rhodopsin were exposed to blue Light, no Damage occurred, in contrast to wild-type control mice. CONCLUSIONS. Short time exposure to blue Light has deleterious effects on retinal morphology. Because Damage was observed only in the presence of the visual pigment, blue-Light‐induced retinal degeneration is rhodopsin mediated. Absorption of blue
-
the rpe65 leu450met variation increases retinal resistance against Light induced degeneration by slowing rhodopsin regeneration
The Journal of Neuroscience, 2001Co-Authors: Andreas Wenzel, Charlotte E Reme, Farhad Hafezi, Theodore P Williams, Christian GrimmAbstract:Excessive Light can cause retinal degeneration and may be an environmental cofactor accelerating retinal dystrophies and age-related diseases. In rodent models, the Light Damage susceptibility (LDS) of the retina is determined genetically. In two mouse strains, with different degrees of LDS, a Leu450Met variation in the pigment epithelial protein RPE65 was shown recently to cosegregate with low LDS. Because Light Damage is rhodopsin-mediated, and RPE65 is essential for the regeneration of rhodopsin in the visual cycle, we analyzed this variation regarding rhodopsin metabolism and LDS in four mouse strains. We found that, in contrast to previous assertions, LDS does not correlate with the maximal retinal content of rhodopsin present after dark adaptation. Instead, LDS correlated positively with the kinetics of rhodopsin regeneration, which determine rhodopsin availability during Light exposure. Light Damage occurred after absorption of a threshold dose of photons and thus fast regeneration, as observed in those two strains having Leu at position 450 of RPE65, was correlated with the occurrence of photoreceptor apoptosis after short exposure. In contrast, mice with the Leu450Met variation of Rpe65 regenerated rhodopsin with slow kinetics and showed an increased resistance to Light-induced retinal degeneration. In these mice, RPE65 protein levels were reduced by a post-transcriptional mechanism. F 1 hybrid mice, carrying one normal and one variant Rpe65 gene, had intermediate levels of the corresponding protein and showed intermediate rhodopsin regeneration kinetics and an intermediate LDS. Thus, none of the two variants of Rpe65 had a dominant effect.
-
protection of rpe65 deficient mice identifies rhodopsin as a mediator of Light induced retinal degeneration
Nature Genetics, 2000Co-Authors: Christian Grimm, Andreas Wenzel, Farhad Hafezi, Shirley Yu, T M Redmond, Charlotte E RemeAbstract:Light-induced apoptosis of photoreceptors represents an animal model for retinal degeneration1. Major human diseases that affect vision, such as age-related macular degeneration (AMD) and some forms of retinitis pigmentosa (RP), may be promoted by Light2,3,4,5,6,7. The receptor mediating Light Damage, however, has not yet been conclusively identified; candidate molecules include prostaglandin synthase8, cytochrome oxidase9, rhodopsin10, and opsins of the cones and the retinal pigment epithelium11 (PE). We exposed to bright Light two groups of genetically altered mice that lack the visual pigment rhodopsin (Rpe65−/− and Rho−/−). The gene Rpe65 is specifically expressed in the PE and essential for the re-isomerization of all-trans retinol in the visual cycle and thus for the regeneration of rhodopsin after bleaching12. Rho−/− mice do not express the apoprotein opsin in photoreceptors, which, consequently, do not contain rhodopsin13. We show that photoreceptors lacking rhodopsin in these mice are completely protected against Light-induced apoptosis. The transcription factor AP-1, a central element in the apoptotic response to Light14,15, is not activated in the absence of rhodopsin, indicating that rhodopsin is essential for the generation or transduction of the intracellular death signal induced by Light.
Andreas Wenzel - One of the best experts on this subject based on the ideXlab platform.
-
rpe65 as a modifier gene for inherited retinal degeneration
European Journal of Neuroscience, 2006Co-Authors: Marijana Samardzija, Andreas Wenzel, M Naash, Charlotte E Reme, Christian GrimmAbstract:Light accelerates progression of retinal degeneration in many animal models of retinitis pigmentosa (RP). A sequence variant in the Rpe65 gene (Rpe65450Leu or Rpe65450Met) can act as a modulator of Light-Damage susceptibility in mice by influencing the kinetics of rhodopsin regeneration and thus by modulating the photon absorption. Depending on exposure duration and Light intensity applied, white fluorescent Light induces photoreceptor apoptosis and retinal degeneration in wild-type mice by the activation of one of two known molecular pathways. These pathways depend, respectively, on activation of the transcription factor c-Fos/AP-1 and on phototransduction activity. Here we tested Rpe65 as a genetic modifier for inherited retinal degeneration and analysed which degenerative pathway is activated in a transgenic mouse model of autosomal dominant RP. We show that retinal degeneration was reduced in mice expressing the Rpe65450Met variant and that these mice retained more visual pigment rhodopsin than did transgenic mice expressing the Rpe65450Leu variant. In addition, lack of phototransduction slowed retinal degeneration whereas ablation of c-Fos had no effect. We conclude that sequence variations in the Rpe65 gene can act as genetic modifiers in inherited retinal degeneration, presumably by regulating the daily rate of photon absorption through the modulation of rhodopsin regeneration kinetics. Increased absorption of photons and/or Light sensitivity appear to accelerate retinal degeneration via an apoptotic cascade which involves phototransduction but not c-Fos.
-
molecular mechanisms of Light induced photoreceptor apoptosis and neuroprotection for retinal degeneration
Progress in Retinal and Eye Research, 2005Co-Authors: Andreas Wenzel, Marijana Samardzija, Christian Grimm, Charlotte E RemeAbstract:Human retinal dystrophies and degenerations and Light-induced retinal degenerations in animal models are sharing an important feature: visual cell death by apoptosis. Studying apoptosis may thus provide an important handle to understand mechanisms of cell death and to develop potential rescue strategies for blinding retinal diseases. Apoptosis is the regulated elimination of individual cells and constitutes an almost universal principle in developmental histogenesis and organogenesis and in the maintenance of tissue homeostasis in mature organs. Here we present an overview on molecular and cellular mechanisms of apoptosis and summarize recent developments. The classical concept of apoptosis being initiated and executed by endopeptidases that cleave proteins at aspartate residues (Caspases) can no longer be held in its strict sense. There is an increasing number of caspase-independent pathways, involving apoptosis inducing factor, endonuclease G, poly-(ADP-ribose) polymerase-1, proteasomes, lysosomes and others. Similarly, a considerable number and diversity of pro-apoptotic stimuli is being explored. We focus on apoptosis pathways in our model: Light-Damage induced by short exposures to bright white Light and highLight those essential conditions known so far in the apoptotic death cascade. In our model, the visual pigment rhodopsin is the essential mediator of the initial death signal. The rate of rhodopsin regeneration defines Damage threshold in different strains of mice. This rate depends on the level of the pigment epithelial protein RPE65, which in turn depends on the amino acid (leucine or methionine) encoded at position 450. Activation of the pro-apoptotic transcription factor AP-1 constitutes an essential death signal. Inhibition of rhodopsin regeneration as well as suppression of AP-1 confers complete protection in our system. Furthermore, we describe observations in other Light-Damage systems as well as characteristics of animal models for RP with particular emphasis on rescue strategies. There is a vast array of different neuroprotective cytokines that are applied in Light-Damage and RP animal models and show diverging efficacy. Some cytokines protect against Light Damage as well as against RP in animal models. At present, the mechanisms of neuroprotective/anti-apoptotic action represent a "black box" which needs to be explored. Even though acute Light Damage and RP animal models show different characteristics in many respects, we hope to gain insights into apoptotic mechanisms for both conditions by studying Light Damage and comparing results with those obtained in animal models. In our view, future directions may include the investigation of different apoptotic pathways in Light Damage (and inherited animal models). Emphasis should also be placed on mechanisms of removal of dead cells in apoptosis, which appears to be more important than initially recognized. In this context, a stimulating concept concerns age-related macular degeneration, where an insufficiency of macrophages removing debris that results from cell death and photoreceptor turnover might be an important pathogenetic event. In acute Light Damage, the appearance of macrophages as well as phagocytosis by the retinal pigment epithelium are a consistent and conspicuous feature, which lends itself to the study of removal of cellular debris in apoptosis. We are aware of the many excellent reviews and the earlier work paving the way to our current knowledge and understanding of retinal degeneration, photoreceptor apoptosis and neuroprotection. However, we limited this review mainly to work published in the last 7-8 years and we apologize to all the researchers which have contributed to the field but are not cited here.
-
rhodopsin mediated blue Light Damage to the rat retina effect of photoreversal of bleaching
Investigative Ophthalmology & Visual Science, 2001Co-Authors: Christian Grimm, Andreas Wenzel, Farhad Hafezi, Theodore P Williams, Pascal Rol, Charlotte E RemeAbstract:METHODS. Eyes of anesthetized rats and mice that did or did not contain rhodopsin were exposed to green (550 6 10 nm) or deep blue (403 6 10 nm) Light for up to 2 hours. Rats with nearly rhodopsinless retinas were obtained by bleaching rhodopsin in animals with inhibited metabolic rhodopsin regeneration—that is, under halothane anesthesia. In addition, Rpe65 2/2 mice that are completely without rhodopsin were used to test the susceptibility to blue-Light Damage of a rodent retina completely devoid of the visual pigment. Effects of illumination on photoreceptor morphology were assessed 24 hours or 10 days thereafter by morphologic and biochemical methods. RESULTS. Exposure to blue Light resulted in severe retinal Damage and activation of the transcription factor AP-1 in rats. In contrast, green Light had no effect. When rhodopsin was almost completely bleached by short-term green-Light exposure while metabolic regeneration (but not photoreversal) was prevented by halothane anesthesia, blue-Light exposure induced distinct lesions in rat retinas. When both metabolic rhodopsin regeneration and photoreversal of bleaching were almost completely inhibited, blue-Light exposure caused only very moderate lesions. When mice without rhodopsin were exposed to blue Light, no Damage occurred, in contrast to wild-type control mice. CONCLUSIONS. Short time exposure to blue Light has deleterious effects on retinal morphology. Because Damage was observed only in the presence of the visual pigment, blue-Light‐induced retinal degeneration is rhodopsin mediated. Absorption of blue
-
the rpe65 leu450met variation increases retinal resistance against Light induced degeneration by slowing rhodopsin regeneration
The Journal of Neuroscience, 2001Co-Authors: Andreas Wenzel, Charlotte E Reme, Farhad Hafezi, Theodore P Williams, Christian GrimmAbstract:Excessive Light can cause retinal degeneration and may be an environmental cofactor accelerating retinal dystrophies and age-related diseases. In rodent models, the Light Damage susceptibility (LDS) of the retina is determined genetically. In two mouse strains, with different degrees of LDS, a Leu450Met variation in the pigment epithelial protein RPE65 was shown recently to cosegregate with low LDS. Because Light Damage is rhodopsin-mediated, and RPE65 is essential for the regeneration of rhodopsin in the visual cycle, we analyzed this variation regarding rhodopsin metabolism and LDS in four mouse strains. We found that, in contrast to previous assertions, LDS does not correlate with the maximal retinal content of rhodopsin present after dark adaptation. Instead, LDS correlated positively with the kinetics of rhodopsin regeneration, which determine rhodopsin availability during Light exposure. Light Damage occurred after absorption of a threshold dose of photons and thus fast regeneration, as observed in those two strains having Leu at position 450 of RPE65, was correlated with the occurrence of photoreceptor apoptosis after short exposure. In contrast, mice with the Leu450Met variation of Rpe65 regenerated rhodopsin with slow kinetics and showed an increased resistance to Light-induced retinal degeneration. In these mice, RPE65 protein levels were reduced by a post-transcriptional mechanism. F 1 hybrid mice, carrying one normal and one variant Rpe65 gene, had intermediate levels of the corresponding protein and showed intermediate rhodopsin regeneration kinetics and an intermediate LDS. Thus, none of the two variants of Rpe65 had a dominant effect.
-
protection of rpe65 deficient mice identifies rhodopsin as a mediator of Light induced retinal degeneration
Nature Genetics, 2000Co-Authors: Christian Grimm, Andreas Wenzel, Farhad Hafezi, Shirley Yu, T M Redmond, Charlotte E RemeAbstract:Light-induced apoptosis of photoreceptors represents an animal model for retinal degeneration1. Major human diseases that affect vision, such as age-related macular degeneration (AMD) and some forms of retinitis pigmentosa (RP), may be promoted by Light2,3,4,5,6,7. The receptor mediating Light Damage, however, has not yet been conclusively identified; candidate molecules include prostaglandin synthase8, cytochrome oxidase9, rhodopsin10, and opsins of the cones and the retinal pigment epithelium11 (PE). We exposed to bright Light two groups of genetically altered mice that lack the visual pigment rhodopsin (Rpe65−/− and Rho−/−). The gene Rpe65 is specifically expressed in the PE and essential for the re-isomerization of all-trans retinol in the visual cycle and thus for the regeneration of rhodopsin after bleaching12. Rho−/− mice do not express the apoprotein opsin in photoreceptors, which, consequently, do not contain rhodopsin13. We show that photoreceptors lacking rhodopsin in these mice are completely protected against Light-induced apoptosis. The transcription factor AP-1, a central element in the apoptotic response to Light14,15, is not activated in the absence of rhodopsin, indicating that rhodopsin is essential for the generation or transduction of the intracellular death signal induced by Light.
Joshua L Dunaief - One of the best experts on this subject based on the ideXlab platform.
-
complement c5a receptor knockout has diminished Light induced microglia macrophage retinal migration
Molecular Vision, 2017Co-Authors: Delu Song, Michael E Sulewski, Chenguang Wang, Jiantao Song, Rupak Bhuyan, Jacob Sterling, Esther Clark, Wenchao Song, Joshua L DunaiefAbstract:Purpose The complement system is involved in the pathogenesis of age-related macular degeneration (AMD). Because activated microglia are also associated with AMD, we studied the relationship between complement anaphylatoxin receptors and microglial recruitment. Methods We assessed the effect of anaphylatoxin C3a receptor (C3aR) and C5a receptor (C5aR) knockout (KO) on Light Damage-induced migration of microglia/macrophages into the mouse outer retina via immunofluorescence and real-time quantitative PCR. Results We found that the mRNA levels of C3, C5, C3aR, C5aR, and two activators of the complement alternative pathway, Cfb and Cfd, were all upregulated after Light exposure. Retinal Iba1-positive microglia/macrophages express receptors for C3a and C5a. Light Damage increased the number of retinal Iba1-positive cells and the mRNA levels of Iba1. Compared with the wild-type (WT) mice, these increases were attenuated in the C5aR KO mice but not in the C3aR KO mice. Conclusions C5aR but not C3aR promoted the recruitment of microglia/macrophages. These divergent properties of complement anaphylatoxins in the Light Damage model provide a rationale for testing the differential effects of these receptors in additional retinal and neurodegeneration models.
-
intraperitoneal injection of epigallocatechin 3 gallate protects against Light induced photoreceptor degeneration in the mouse retina
Molecular Vision, 2017Co-Authors: Chenguang Wang, Delu Song, Ying Song, Joshua L DunaiefAbstract:PURPOSE (-)-epigallocatechin-3-gallate (EGCG), a major catechin component of green tea, is reported to delay or prevent certain forms of cancer, arthritis, cardiovascular disease, and neurodegenerative disorders. In this study, we determined if systemically administered EGCG could protect the retina against Light Damage (LD) in mice. METHODS BALB/cJ mice were treated with either EGCG or saline via intraperitoneal (IP) injection, and then placed under constant cool white Light-emitting diode (LED) Light (10,000 lux) for 5 h. Retinal structure and function were evaluated using optical coherence tomography (OCT), histology, and electroretinography (ERG) 7 days after LD. In addition, the mRNAs of several oxidative stress genes were quantified by qPCR before LD and 24 h after LD. RESULTS OCT and photomicrographs of mouse retinas showed morphologic protection of photoreceptors. Mice in the EGCG group had significantly higher ERG amplitudes for all three wave types compared with mice in the saline control group, which indicated that EGCG protected retinal function. Furthermore, qPCR results showed that EGCG administration can increase the mRNA level of the antioxidant gene Sod2 before LD and 24 h after LD. CONCLUSIONS The IP injection of EGCG attenuated the detrimental effects of bright Light on the retinas of BALB/cJ mice by protecting the structure and function of the retina.
-
microarray analysis of murine retinal Light Damage reveals changes in iron regulatory complement and antioxidant genes in the neurosensory retina and isolated rpe
Investigative Ophthalmology & Visual Science, 2012Co-Authors: Majda Hadziahmetovic, Delu Song, John W Tobias, Usha Kumar, Ying Song, Steven Grieco, Yafeng Li, Joshua L DunaiefAbstract:PURPOSE: The purpose of this study was to investigate Light Damage-induced transcript changes within neurosensory retina (NSR) and isolated retinal pigment epithelium (RPE). Similar studies have been conducted previously, but were usually limited to the NSR and only a portion of the transcriptome. Herein most of the transcriptome, not just in the NSR but also in isolated RPE, was queried. METHODS: Mice were exposed to 10,000 lux cool white fluorescent Light for 18 hours and euthanized 4 hours after photic injury. NSR and isolated RPE were collected, and RNA was isolated. DNA microarray hybridization was conducted as described in the Affymetrix GeneChip Expression Analysis Technical Manual. Microarray analysis was performed using probe intensity data derived from the Mouse Gene 1.0 ST Array. For the genes of interest, confirmation of gene expression was done using quantitative real-time PCR. Immunofluorescence assessed protein levels and localization. RESULTS: Numerous iron regulatory genes were significantly changed in the Light-exposed NSR and RPE. Several of these gene expression changes favored an iron-overloaded state. For example, the transferrin receptor was upregulated in both Light-exposed NSR and RPE. Consistent with this, there was stronger transferrin receptor immunoreactivity in the Light-exposed retinas. Significant changes in gene expression following Light Damage were also observed in oxidative stress and complement system genes. CONCLUSIONS: The concept of a photooxidative stress-induced vicious cycle of increased iron uptake leading to further oxidative stress was introduced.
-
Light Damage induced changes in mouse retinal gene expression
Experimental Eye Research, 2004Co-Authors: Lin Chen, Tzvete Dentchev, Yong Zeng, Jianhua Wang, Irena Tsui, John W Tobias, Jean Bennett, Donald A Baldwin, Joshua L DunaiefAbstract:Oxidative stress plays a role in the Light Damage model of retinal degeneration as well as in age-related macular degeneration. The purpose of this study is to identify retinal genes induced by acute photo-oxidative stress, which may function as mediators of apoptosis or as survival factors. To accomplish this, Balb/c mice were exposed to bright cool white fluorescent Light for 7 hr. Retinas were then isolated for total RNA preparation followed by Affymetrix DNA microarray analysis to compare gene expression in Light Damaged mice to unexposed controls. Three independent Light Damage experiments were carried out and statistical filters were applied to detect genes with expression changes averaging at least two-fold. Quantitative PCR was carried out to confirm altered gene expression. Seventy genes were upregulated at least two-fold immediately following Light Damage. QPCR confirmed upregulation of all 10 genes tested. The upregulated genes fall into several categories including antioxidants: ceruloplasmin, metallothionein, and heme oxygenase; antiapoptotic gene: bag3, chloride channels: clic1 and clic4; transcription factors: c-fos, fra1, junB, stat1, krox-24 and c/ebp; secreted signaling molecules: chitinase 3-like protein 1 and osteopontin; inflammation related genes: MCP-1 and ICAM1 and others. Upregulation of five interferon-gamma responsive genes suggests elevated interferon levels after Light Damage. Upregulation of three components of the AP-1 transcription factor is consistent with previous evidence implicating AP-1 in Light Damage pathogenesis. Four copper or iron binding proteins were upregulated, suggesting that photo-oxidative stress may affect metal homeostasis. The genes found upregulated by Light Damage may affect the survival of photoreceptors subjected to photo-oxidative stress.
Ian Constable - One of the best experts on this subject based on the ideXlab platform.
-
lipofuscin of the retinal pigment epithelium a review
Eye, 1995Co-Authors: Christopher J Kennedy, Piroska E Rakoczy, Ian ConstableAbstract:Accumulation of lipofuscin is one of the most characteristic features of ageing observed in retinal pigment epithelial (RPE) cells. The lipofuscin found in RPE cells differs from that of other body tissues due to the fact that it is mainly derived from the chemically modified residues of incompletely digested photoreceptor outer segments. It is a heterogeneous material composed of a mixture of lipids, proteins, and different fluorescent compounds, the main fluorophore of which has recently been identified as a derivative of vitamin A. Research interest has variously focussed on the roles of age, Light Damage, free radicals, antioxidants, visual pigments, retinal locus, lysosomal enzymes, and pigmentation on lipofuscin formation, as well as the effects of lipofuscin on RPE cell function and causation of retinal disease. This article reviews the recent advances in knowledge of the composition, origin, and possible deleterious effects of RPE cell lipofuscin.