Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda, Keiko; Zhao, Jin; Kim, Hye Jin; Sparrow, Janet R.

doi:10.1073/pnas.1524774113

Cited by 93 publications

(129 citation statements)

References 62 publications

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“…This molecule has been described to be involved in the pathogenesis of age-related macular degeneration (AMD) [52,53] and Stargardt disease [54]. A2E is known to be able to produce cytotoxicity by destabilizing membranes, generating reactive oxygen species and producing photo-oxidation [55][56][57][58].…”

Section: Future Directionsmentioning

confidence: 99%

Interphotoreceptor Retinoid-Binding Protein Implications in Diabetic Retinopathy

Bermea¹

2018

Early Events in Diabetic Retinopathy and Intervention Strategies

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The interphotoreceptor retinoid-binding protein (IRBP) is the most abundant protein in the interphotoreceptor matrix (IPM) and its levels decrease beginning in the early stages of diabetes. IRBP participates in the delivery of retinoids between retinal cells to carry out the visual cycle and also protects those retinoids against degradation in the IPM. IRBP deficiency is related to several conditions such as retinitis pigmentosa, cone-rod dystrophy, increased oxidative stress in the photoreceptors, and myopia. Decreased IRBP levels in diabetes could be due to the secretion of inflammatory cytokines and a direct effect of hyperglycemia on the photoreceptors. It is known that prior to the occurrence of vascular changes in diabetic retina, electrophysiological alterations occur on early potentials. Alterations on the photoreceptor outer segments and increased oxidative stress indicate an important affliction of the photoreceptors from early stages. Due to the importance of IRBP in photoreceptor wellness, its decreased levels may be linked to early photoreceptor affection. More studies are required to describe in detail the whole impact that decreased levels of IRBP in diabetes may have.

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Section: Future Directionsmentioning

confidence: 99%

Interphotoreceptor Retinoid-Binding Protein Implications in Diabetic Retinopathy

Bermea¹

2018

Early Events in Diabetic Retinopathy and Intervention Strategies

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“…More recently Ref. [56] showed that RPE-lipofuscin photodegradation takes place in mouse eyes under standard ambient illumination. Speciically, they found that WT and ABCA4 −/− mice reared in constant darkness contained 45 and 62% more LBs in the RPE than their respective 12-h cyclic light-reared controls.…”

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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“…The primary amine of PE in photoreceptor cell outer segments is notable for being subject to the reactivity of vitamin A aldehyde (all-trans-retinal or 11-cis-retinal) (6) that is essential to photon absorption by photoreceptor cells . The resulting Schiff base adduct, N-retinylidene-PE (NRPE) (7) serves to chaperone reactive retinaldehyde until it is reduced to all-trans-retinol by NADPH-dependent retinol 4 reaction is a [1,6]-proton tautomerization generating a phosphatidylethanolamine-retinyl enamine, which reacts with the second retinaldehyde.…”

Section: Introductionmentioning

confidence: 99%

“…The resulting Schiff base adduct, N-retinylidene-PE (NRPE) (7) serves to chaperone reactive retinaldehyde until it is reduced to all-trans-retinol by NADPH-dependent retinol 4 reaction is a [1,6]-proton tautomerization generating a phosphatidylethanolamine-retinyl enamine, which reacts with the second retinaldehyde. After aza-6π-electrocyclization and auto-oxidation of the dihydroopyridinium intermediate (dihydro-A2PE) (12) the fluorescent phosphatidyl-pyridinium bisretinoid A2PE is formed.…”

Section: Introductionmentioning

confidence: 99%

Novel bisretinoids of human retina are lyso alkyl ether glycerophosphoethanolamine-bearing A2PE species

Kim

Sparrow

2018

Journal of Lipid Research

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Bisretinoids are a family of fluorophores that form in photoreceptor cells outer segments by nonenzymatic reaction of two vitamin A aldehyde (A2) with phosphatidylethanolamine (PE). Bisretinoids fluorophores are the major constituents of the lipofuscin of retinal pigment epithelium (RPE) that accumulates with age and contributes to some retinal diseases. Here, we report the identification of a previously unknown fluorescent bisretinoid. By ultra-performance-liquid-chromatography coupled to photodiode-array detection, fluorescence and electrospray-ionization-mass-spectrometry (UPLC-PDA-FLR-ESI-MS), we determined that this novel bisretinoid is 1-octadecyl-2-lyso-sn-glycero A2PE (alkyl ether lysoA2PE). This structural assignment was based on molecular mass (m/z 998), UV-visible absorbance maxima (340, 440 nm) and retention time (73 minutes) and was corroborated by biomimetic synthesis using all-trans-retinal and glycerophosphoethanolamine analogues as starting materials. UPLC profiles of ocular extracts acquired from human donor eyes revealed that alkyl ether lysoA2PE was detectable in RPE but not neural retina. LysoA2PE fluorescence spectra exhibited a significant hyperchromic shift in hydrophobic environments. Propensity for lysoA2PE to undergo photooxidation/degradation was less pronounced than A2E. In mechanistic studies, A2PE was hydrolyzed by PLA2 and plasmalogen lysoA2PE was cleaved under acidic conditions. The characterization of these additional members of the bisretinoid family advances our understanding of mechanisms underlying bisretinoid biogenesis.

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Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Cited by 93 publications

References 62 publications

Interphotoreceptor Retinoid-Binding Protein Implications in Diabetic Retinopathy

Interphotoreceptor Retinoid-Binding Protein Implications in Diabetic Retinopathy

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

Novel bisretinoids of human retina are lyso alkyl ether glycerophosphoethanolamine-bearing A2PE species

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