Superoxidation of Bisretinoids

Washington, Ilyas; Jockusch, Steffen; Itagaki, Yasuhiro; Turro, Nicholas J.; Nakanishi, Koji

doi:10.1002/anie.200501346

Cited by 30 publications

(15 citation statements)

References 23 publications

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“…Using in vitro models, vitamin A dimers have been shown to destabilize lipid membranes (54), act as a retinoid X receptor (RXR) agonist (55), act as RPE65 antagonist, activate the complement cascade (56), inhibit cholesterol metabolism (57), deactivate mitochondria, inhibit phagocytosis (58), act as pro-oxidants (59), associate with DNA (60, 61) and form peroxides (62,63). Nevertheless, whether vitamin A dimers contribute to, are merely a symptom of, or even protect against retinal degeneration is still controversial (64,65).…”

Section: Discussionmentioning

confidence: 99%

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

Kaufman

Zhang

et al. 2011

Journal of Biological Chemistry

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Autosomal recessive Stargardt disease (STGD1) is a macular dystrophy resulting from mutations in the ABCA4 (ABCR) gene. The age of onset of Stargardt disease is typically 10 -20 years of age and leads in almost all cases to blindness by age 50 (1, 2). A hallmark of the disease is premature lipofuscin accumulation in the retinal pigment epithelium (RPE) 2 of the eye. The RPE is critical for the neurosensory retina homeostasis; it acts as a transport exchange system with blood capillaries and is critical for regeneration and phagocytosis of photoreceptor outer segments. It is hypothesized that when RPE lipofuscin reaches a critical level, it contributes to a decline in cell function (3-8) resulting in the degeneration of the macular region of the neurosensory retina leading to loss of central vision (9 -11).The defective gene in Stargardt, ABCA4, encodes for an outer segment rim protein (RmP). The function of RmP is to transport the all-trans-retinaldehyde-phosphatidylethanolamine (retinaldehyde-PE) Schiff base from the luminal side of the disk membrane to the cytosolic face, where retinaldehyde can then be converted back to retinol (3). In the absence of its proper transporter, the retinaldehyde-PE conjugates may react to form vitamin A dimers (A2E and ATR-dimer among others), which are then deposited in the RPE after phagocytosis of the photoreceptors outer segments. Numerous studies have demonstrated the toxicity of vitamin A dimers to cultured RPE cells and they are hypothesized to play a key role in lipofuscin formation and subsequent retinal degeneration (12, 13). Nevertheless, the exact mechanisms that lead to lipofuscin accumulation or to vision loss as a result of the impaired transport of the retinaldehyde-PE conjugates remain unclear.In the accompanying article, we have shown that the ratedetermining step in vitamin A dimerization is the cleavage of a C20 carbon-hydrogen bond of the retinaldehyde-PE Schiff base (14). Replacing the C20 hydrogen atoms of vitamin A with deuterium atoms (i.e. C20-D 3 -vitamin A) makes this bond harder to cleave and impedes vitamin A dimerization (14). In this study we sought to determine whether retarding the intrinsic reactivity of vitamin A to dimerize could slow lipofuscin formation in the RPE and delay changes associated with human Stargardt disease. To accomplish this we raised ABCA4 Ϫ/Ϫ mutant albino mice (the mouse model of human Stargardt's disease) on diets containing either C20-D 3 -vitamin A (the treated group) or vitamin A at its natural isotopic abundance (the control group) and measured the concentration of vitamin A dimers, lipofuscin and other biological markers indicative of ocular health in both groups. Treated mice exhibited an 80% reduction in A2E, a 95% reduction in ATR dimer and a 70% decrease in fundus autofluorescence at three months of age. After six months, the treated group showed fewer lipofuscin granules as visualized qualitatively by electron microscopy, and at 12 months they showed improved eye function as measured by electroretinogram (ERG). ...

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Section: Discussionmentioning

confidence: 99%

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

Kaufman

Zhang

et al. 2011

Journal of Biological Chemistry

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“…3 In rodent models of macular degeneration, 4, 5, 6, 7, 8 high levels of vitamin A dimers correlate with poor retinal health and a variety of mechanisms have been proposed by which dimers of vitamin A may induce retinal toxicity ranging from non specific to direct antagonistic/protagonistic mechanisms. 9, 10, 11, 12, 13, 14, 15, 16 As a cationic ambiphilic pyridinium, A2E has been shown to solubilize lipid membranes, inactivate lysosomes by increasing lysosomal pH, and accumulates in the negatively charged mitochondrial compartment. Once dimerized, the special orientation of the polyene chains make them especially susceptible to oxidative degradation 16 leading to secondary reactive aldehyde and epoxide toxicants.…”

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confidence: 99%

“…9, 10, 11, 12, 13, 14, 15, 16 As a cationic ambiphilic pyridinium, A2E has been shown to solubilize lipid membranes, inactivate lysosomes by increasing lysosomal pH, and accumulates in the negatively charged mitochondrial compartment. Once dimerized, the special orientation of the polyene chains make them especially susceptible to oxidative degradation 16 leading to secondary reactive aldehyde and epoxide toxicants. 17 Direct reported mechanisms of A2E toxicity include, acting as an agonist for retinal pigment epithelium-specific 65-kDa protein, 18 retinoic acid receptors, 10 cyclooxygenase-2, 19 and covalent modification of biomolecules, 20, 21 among others.…”

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confidence: 99%

“…More recently, based on studies in ARPE-19 cells, it has been proposed that A2E's chemical precursor, vitamin A aldehyde (retinaldehyde), might play a role in the degenerative process and that A2E might be a benign biomarker of increased levels of retinaldehyde. 16, 17, 18 To determine if A2E could chemically trigger the degenerative process in the retina, we explored the acute and long-term toxicity of A2E to human retinal pigment epithelium (RPE) cells in vitro . ARPE-19 cells treated with A2E showed degraded mitochondria, accumulated glycogen and lipofuscin debris, and underwent a protracted, dose-dependent death over several days to months.…”

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Vitamin A dimers trigger the protracted death of retinal pigment epithelium cells

Mihai

Washington

2014

Cell Death Dis

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Cellular events responsible for the initiation of major neurodegenerative disorders of the eye leading to blindness, including age-related macular degeneration, Stargardt and Best diseases, are poorly understood. Accumulation of vitamin A dimers, such as N-retinylidene-N-retinylethanolamine (A2E) in the retinal pigment epithelium (RPE), is one of the earliest measurable events preceding retinal degeneration. However, the extent to which these dimers contribute to tissue degeneration is not clear. To determine if A2E could trigger morphological changes associated with the degenerating RPE and subsequent cell death, we evaluated its toxicity to cultured human RPE cells (ARPE-19). We show that A2E triggered the accumulation of debris followed by a protracted death. A2E was up to≈14-fold more toxic than its precursor, retinaldehyde. Measurements reveal that the concentration of A2E in the aged human eye could exceed the concentration of all other retinoids, opening the possibility of A2E-triggered cell death by several reported mechanisms. Findings suggest that accumulation of vitamin A dimers such as A2E in the human eye might be responsible for the formation of ubiquitous RPE debris, an early indication of retinal degeneration, and that preventing or reducing the accumulation of vitamin A dimers is a prudent strategy to prevent blindness.

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“…Cellular photosensitivity is proportional to the amount of LBs accumulated [42] and the wavelength, with a maximum at 430 nm (blue light), which coincides with the excitation spectrum of the LBs [43]. The absorption of blue photons by the LBs' extended double bond conjugated system, in the presence of oxygen, leads to the formation of oxidized LB species [44,45] that after repetitive oxidative atacks become fragmented into far reaching, highly reactive, carbonyl bearing small molecules [43,44,[46][47][48]. These fragments promote cell damage by forming Schif base adducts with free amine groups in lysosomal hydrolases, nucleotides, phospholipids, lipids, proteins [49], DNA [50], proteasomes [51], and molecules in extracellular retinal deposits (drusen), which could trigger local innate and adaptive immune responses [52,53].…”

Section: Phototoxicitymentioning

confidence: 95%

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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Superoxidation of Bisretinoids

Abstract: Up close and personal: Intimate retinoid polyenes, shown on the right chair, were found to react readily with oxygen (shown in red) to give the polyoxygenated species. On the other hand, when the polyenes are separated, shown on the left sofa, the oxidation is limited.

Cited by 30 publications

References 23 publications

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

C20-D3-vitamin A Slows Lipofuscin Accumulation and Electrophysiological Retinal Degeneration in a Mouse Model of Stargardt Disease

Vitamin A dimers trigger the protracted death of retinal pigment epithelium cells

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

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