Blue Light-induced Reactivity of Retinal Age Pigment

Różanowska, Malgorzata Barbara; Jarvis-Evans, J.; Korytowski, Witold; Boulton, Mike; Burke, Janice M.; Sarna, Tadeusz

doi:10.1074/jbc.270.32.18825

Cited by 392 publications

(136 citation statements)

References 21 publications

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“…A2E was shown to form oxiranes in vitro by addition of singlet oxygen (29). Further, lipofuscin was shown to generate reactive oxygen species, including singlet oxygen, on exposure to blue light (39). Thus, the A2E-laden RPE in abcr Ϫ/Ϫ mice exposed to bright light should strongly promote formation of oxiranes.…”

Section: Discussionmentioning

confidence: 99%

Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration

Radu

Mata

Bagla

et al. 2004

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

149

119

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Recessive Stargardt's macular degeneration is a blinding disease of children caused by mutations in the ABCA4 (ABCR) gene. Mice with a knockout mutation in abcr accumulate toxic lipofuscin pigments in ocular tissues, similar to affected humans. The major fluorophore of lipofuscin is the bis-retinoid, N-retinylidene-N-retinylethanolamine (A2E). In the current study, we sought to define the effect of increasing light on A2E accumulation. We crossed the abcr Ϫ/Ϫ mutation onto an albino background. The retinoid profiles in albino mice indicated higher retinal illuminance than in pigmented mice exposed to similar ambient light. Unexpectedly, A2E levels were not higher in the albino mice. Also, A2E levels in abcr Ϫ/Ϫ mice reared under cyclic light at 30, 120, or 1,700 lux were similar. Thus, increased retinal illuminance was not correlated with higher A2E. A2E has been shown to undergo light-dependent oxidation to yield a series of A2E epoxides or oxiranes. These oxiranes react with DNA in vitro, suggesting a potential mechanism for A2E cytotoxicity. We analyzed ocular tissues from abcr Ϫ/Ϫ mice for A2E oxiranes by mass spectrometry. Unlike A2E, the oxiranes were more abundant in albino vs. pigmented abcr Ϫ/Ϫ mice, and in abcr Ϫ/Ϫ mice exposed to increasing ambient light. These observations suggest that both the biosynthesis of A2E and its conversion to oxiranes are accelerated by light. Finally, we showed that the formation of A2E oxiranes is strongly suppressed by treating the abcr Ϫ/Ϫ mice with Accutane (isotretinoin), an inhibitor of rhodopsin regeneration.

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Section: Discussionmentioning

confidence: 99%

Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration

Radu

Mata

Bagla

et al. 2004

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

149

119

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“…Lipofuscin is a mixture of nondegradable protein-lipid aggregates derived from the ingestion of photoreceptor outer segments (5). A2E is the major fluorophore of lipofuscin and acts as a photosensitizer to generate reactive oxygen species inside the cells upon exposure to blue light (5)(6)(7). An increasing body of literature indicates that oxidative stress and dysfunction of RPE are associated with the pathogenesis of AMD (8 -10), the leading cause of blindness in industrialized countries.…”

mentioning

confidence: 99%

Oxidative Inactivation of the Proteasome in Retinal Pigment Epithelial Cells

Fernandes

Zhou

Zhang

et al. 2008

Journal of Biological Chemistry

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Oxidative stress and inflammation are implicated in the pathogenesis of many age-related diseases. Stress-induced overproduction of inflammatory cytokines, such as interleukin-8 (IL-8), is one of the early events of inflammation. The objective of this study was to elucidate mechanistic links between oxidative stress and overproduction of IL-8 in retinal pigment epithelial (RPE) cells. We found that exposure of RPE cells to H 2 O 2 , paraquat, or A2E-mediated photooxidation resulted in increased expression and secretion of IL-8. All of these oxidative stressors also inactivated the proteasome in RPE cells. In contrast, tert-butylhydroperoxide (TBH), a lipophilic oxidant that did not stimulate IL-8 production, also did not inactivate the proteasome. Moreover, prolonged treatment of RPE cells with proteasome-specific inhibitors recapitulated the stimulation of IL-8 production. These data suggest that oxidative inactivation of the proteasome is a potential mechanistic link between oxidative stress and up-regulation of the proinflammatory IL-8. The downstream signaling pathways that govern the production of IL-8 include NF-B and p38 MAPK. Proteasome inhibition both attenuated the activation and delayed the turnoff of NF-B, resulting in biphasic effects on the production of IL-8. Prolonged proteasome inhibition (>2 h) resulted in activation of p38 MAPK via activation of MKK3/6 and increased the production of IL-8. Chemically inhibiting the p38 MAPK blocked the proteasome inhibition-induced up-regulation of IL-8. Together, these data indicate that oxidative inactivation of the proteasome and the related activation of the p38 MAPK pathway provide a potential link between oxidative stress and overproduction of proinflammatory cytokines, such as IL-8.Oxidative stress, which refers to cellular damage caused by reactive oxygen species, has been implicated in the onset and progression of many age-related diseases, including age-related macular degeneration (AMD), 3 arthritis, atherosclerosis, and certain types of cancer (1-3). Inflammatory events are also known to participate in the pathogenesis of these age-related diseases. The activation of redox-sensitive transcription factors may be involved in triggering the expression of proinflammatory cytokines (2). However, the molecular links between oxidative stress and inflammation are not fully understood.Retina has the highest metabolic rate and oxygen consumption in the body. The high metabolic rate and oxygen consumption is usually accompanied by generation of reactive oxygen species. Chronic exposure to light could also increase the production of reactive oxygen species (1, 4). Therefore, retinal pigment epithelium (RPE) is a primary target of oxidative stress.Age-related accumulation of lipofuscin in RPE is another source of oxidative stress. Lipofuscin is a mixture of nondegradable protein-lipid aggregates derived from the ingestion of photoreceptor outer segments (5). A2E is the major fluorophore of lipofuscin and acts as a photosensitizer to generate reactive oxygen spe...

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“…In vitro data with both, whole lipofuscin granules [39] There is also in vivo evidence indicating that RPE lipofuscin undergoes photodegradation in the eye. Ueda et al [55] showed that ABCA4 −/− animals were more susceptible to light damage than WT animals and that in both groups, older animals carrying larger amounts of LBs were also more susceptible.…”

Section: Phototoxicitymentioning

confidence: 99%

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

Nociari¹,

Kiss²,

Rodríguez-Boulan³

2017

Lysosomes - Associated Diseases and Methods to Study Their Function

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Photoreceptors undergo a constant renewal of their light sensitive outer segments (POSs). In the renewal process, 10% of the POS mass is daily phagocytized by the adjacent retinal pigment epithelium (RPE). POS contain vast amounts of 11-cis retinal and alltrans-retinal, two highly reactive vitamin A aldehydes that spontaneously dimerize into lipid bisretinoids (LBs) and accumulate into RPE lysosomes during phagocytosis. As LBs are refractory to lysosomal hydrolases and RPE cells do not divide, this accumulation is irreversible and results in the formation of lipofuscin granules. Lipofuscin accumulation is toxic for RPE cells through a variety of light-dependent and light-independent mechanisms. Beyond a threshold, RPE cells die resulting in secondary loss of overlying photoreceptors. Currently, there are no efective treatments for retinal disorders associated with genetic or age-associated LB accumulation, such as Stargardt disease and age-related macular degeneration (AMD). Thus, there is a great need for medical interventions. Here, we discuss the current understanding of lipofuscin's pathogenicity and the status of diferent strategies under development to promote LB elimination from RPE lysosomes.Keywords: lipofuscin, Stargardt, age-related macular degeneration (AMD), bisretinoids, retinal pigment epithelium (RPE), cyclodextrins, cellular clearance, TFEB, lysosome IntroductionTo understand the origin and consequences of the lysosomal accumulation of lipofuscin in the eye, a basic knowledge of retinal function and organization is required.© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The retinal pigment epithelium (RPE) in vertebrate's eyesLight entering the eye gets refracted by the cornea and lens on the neural retina, where photoreceptors (PR) convert photons into a cascade of chemical and electrical events that propagate to second-order (horizontal, bipolar, and amacrine cells) and third-order (ganglion cells) retinal neurons, which distribute this information to various visual centers of the brain through the ibers of the optic nerve. The bodies of PR cells, rods and cones, display three sectors (Figure 1): the outer segment, illed with stacks of disks densely packed with light-sensitive photopigment; the inner segment, illed with genetic, biosynthetic, and metabolic organelles Lysosomes -Associated Diseases and Methods to Study Their Function 4(nucleus, endoplasmic reticulum, Golgi complex, ribosomes, mitochondria); and the synaptic terminal that connects with bipolar neurons of the retina. In vertebrates, the retina is inverted in the sense that light passes through secondary and tertiary neuronal layers in the inner retina before reaching the rods and cones in the outer retina (Figure 1). Photoreceptors are metabolically very active cells that req...

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Blue Light-induced Reactivity of Retinal Age Pigment

Cited by 392 publications

References 21 publications

Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration

Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration

Oxidative Inactivation of the Proteasome in Retinal Pigment Epithelial Cells

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

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