Hyperlipofuscinosis and Subretinal Fibrosis in Stargardtʼs Disease

Laey, J. J. De; Verougstraete, Claire

doi:10.1097/00006982-199515050-00005

Cited by 34 publications

(34 citation statements)

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“…dihydro-N-retinylidene-N-retinylphosphatidylethanolamine) in photoreceptor cells and its subsequent conversion and accumulation in the form of A2E in RPE, as indicated by fundus autofluorescence, precedes macular degeneration and visual loss in age-related macular degeneration and Stargardt disease (57). Strong autofluorescence within the retina also is observed in patients with Best vitelliform macular dystrophy and a subset of patients diagnosed with cone-rod dystrophy (58).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina

Golczak

Maeda

Bereta

et al. 2008

Journal of Biological Chemistry

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In vertebrate retinal photoreceptors, the absorption of light by rhodopsin leads to photoisomerization of 11-cis-retinal to its all-trans isomer. To sustain vision, a metabolic system evolved that recycles all-trans-retinal back to 11-cis-retinal. The importance of this visual (retinoid) cycle is underscored by the fact that mutations in genes encoding visual cycle components induce a wide spectrum of diseases characterized by abnormal levels of specific retinoid cycle intermediates. In addition, intense illumination can produce retinoid cycle by-products that are toxic to the retina. Thus, inhibition of the retinoid cycle has therapeutic potential in physiological and pathological states. Four classes of inhibitors that include retinoid and nonretinoid compounds have been identified. We investigated the modes of action of these inhibitors by using purified visual cycle components and in vivo systems. We report that retinylamine was the most potent and specific inhibitor of the retinoid cycle among the tested compounds and that it targets the retinoid isomerase, RPE65. Hydrophobic primary amines like farnesylamine also showed inhibitory potency but a short duration of action, probably due to rapid metabolism. These compounds also are reactive nucleophiles with potentially high cellular toxicity. We also evaluated the role of a specific proteinmediated mechanism on retinoid cycle inhibitor uptake by the eye. Our results show that retinylamine is transported to and taken up by the eye by retinol-binding protein-independent and retinoic acid-responsive gene product 6-independent mechanisms. Finally, we provide evidence for a crucial role of lecithin: retinol acyltransferase activity in mediating tissue specific absorption and long lasting therapeutic effects of retinoid-based visual cycle inhibitors.In vertebrate photoreceptor cells, absorbance of light by the visual chromophore, 11-cis-retinal, coupled to rhodopsin leads to its photoisomerization to all-trans-retinal and initiation of the phototransduction signal cascade (reviewed in Ref. 1). To ensure constant vision, 11-cis-retinal is efficiently regenerated by a complex sequence of enzymatic reactions called the visual or retinoid cycle (reviewed in Refs. 2-4). This pathway is located in both retinal pigment epithelium (RPE) 3 and photoreceptor cells. The key enzymatic step of visual chromophore regeneration is the isomerization of all-trans-retinyl palmitate and other esters to 11-cis-retinol in a reaction catalyzed by RPE65 (5-7).The importance of the retinoid cycle for maintaining vision is documented by the number and variety of diseases caused by mutations in genes encoding proteins involved in this process (2). Three main strategies have been developed to treat these diseases. The first uses virally mediated transfer gene technology to replace the defective gene. This approach has successfully rescued vision in mouse and dog models of Leber congenital amaurosis and retinitis pigmentosa (8 -13). The second approach involving pharmacological supplementation...

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Section: Discussionmentioning

confidence: 99%

Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina

Golczak

Maeda

Bereta

et al. 2008

Journal of Biological Chemistry

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“…Ultimately, the disease Funduscopic examination of the retina in Stargardt patients shows a macular lesion surrounded by irregular yellow-white flecks or spots, which give rise to the alternate name for this disease, fundus flavimaculatus. Histologically, Stargardt disease is characterized by the accumulation of fluorescent lipofuscin pigments in cells of the RPE, degeneration of the RPE, and death of photoreceptors (96,110). Stargardt disease patients commonly show a "dark choroid" during fluorescein angiography due to this light-absorbing lipofuscin material in the RPE (111).…”

Section: Stargardt Macular Degenerationmentioning

confidence: 99%

“…Accumulation of fluorescent lipofuscin pigments in cells of the RPE is an important pathological feature of Stargardt disease (96,110). These pigments are responsible for the "dark choroid" seen during fluorescein angiography (111) and the fundus autofluorescence seen by scanning laser ophthalmoscopy (112).…”

Section: Retinoid Inhibitors Of A2e Formationmentioning

confidence: 99%

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

Travis

Golczak

Moise

et al. 2007

Annu. Rev. Pharmacol. Toxicol.

370

452

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Absorption of a photon by an opsin pigment causes isomerization of the chromophore from 11-cisretinaldehyde to all-trans-retinaldehyde. Regeneration of visual chromophore following light exposure is dependent on an enzyme pathway called the retinoid or visual cycle. Our understanding of this pathway has been greatly facilitated by the identification of disease-causing mutations in the genes coding for visual cycle enzymes. Defects in nearly every step of this pathway are responsible for human-inherited retinal dystrophies. These retinal dystrophies can be divided into two etiologic groups. One involves the impaired synthesis of visual chromophore. The second involves accumulation of cytotoxic products derived from all-trans-retinaldehyde. Gene therapy has been successfully used in animal models of these diseases to rescue the function of enzymes involved in chromophore regeneration, restoring vision. Dystrophies resulting from impaired chromophore synthesis can also be treated by supplementation with a chromophore analog. Dystrophies resulting from the accumulation of toxic pigments can be treated pharmacologically by inhibiting the visual cycle, or limiting the supply of vitamin A to the eyes. Recent progress in both areas provides hope that multiple inherited retinal diseases will soon be treated by pharmaceutical intervention.

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“…One of the major components of RPE lipofuscin has been characterized as N-retinylidene-N-retinylethanolamine (A2E), a pyridinium bis-retinoid and photoinducible free-radical generator (8,9). While human RPE in general accumulates lipofuscin with age, excessive lipofuscin accumulation is associated with a variety of hereditary retinal degenerations (10)(11)(12) and may correlate with ARMD (4).…”

mentioning

confidence: 99%

The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium

Finnemann

Leung

Rodríguez-Boulan

2002

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

259

191

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Daily phagocytosis of spent photoreceptor outer segments is a critical maintenance function performed by the retinal pigment epithelium (RPE) to preserve vision. Aging RPE accumulates lipofuscin, which includes N-retinylidene-N-retinylethanolamine (A2E) as the major autofluorescent component. We studied the effect of physiological levels of A2E in RPE cultures on their ability to phagocytose outer segments. A2E localized to lysosomes in cultured RPE as well as in human RPE in situ. A2E-loaded RPE cells in culture bound and internalized identical numbers of outer segments as control RPE indicating that A2E does not alter early steps of phagocytosis. A2E-loaded RPE degraded outer segment proteins efficiently but, strikingly, failed to completely digest phospholipids within 24 h. Because of the circadian rhythm of RPE phagocytosis in the eye, a delay in lipid degradation would likely result in a build up of undigested material in RPE that could contribute to the development of age-related macular degeneration.A ge-related macular degeneration (ARMD) is a degenerative disease that causes severe visual impairment in one fourth of the population over 65. Some predisposing genetic and environmental factors, such as oxidative stress, low eye pigmentation, excessive light exposure, and smoking, have been identified (1-3). However, the mechanisms underlying the pathogenesis of the disease remain largely obscure.Clinical and histopathological analysis of diseased eyes suggests that alterations in the retinal pigment epithelium (RPE) are key determinants of the disease (4). The most profound change of human RPE with age is the accumulation in the cytoplasm of lipofuscin granules, storage bodies with an autofluorescent mixture of lipids arising from incomplete digestion of phagocytosed photoreceptor (PR) outer segment (OS) membranes (5-7). One of the major components of RPE lipofuscin has been characterized as N-retinylidene-N-retinylethanolamine (A2E), a pyridinium bis-retinoid and photoinducible free-radical generator (8, 9). While human RPE in general accumulates lipofuscin with age, excessive lipofuscin accumulation is associated with a variety of hereditary retinal degenerations (10-12) and may correlate with ARMD (4).The identification and efficient synthetic production of A2E have enabled studies on the consequences of lipofuscin accumulation for RPE function (8, 9, 13). The chemical structure of A2E indicates that it may act as a lysosomotropic agent, abolishing the acidic pH gradient required for normal lysosome function. Indeed, Holz et al. reported that A2E accumulation alone is sufficient to inhibit the lysosomal turnover of endogenous proteins in cultured RPE (14). On the other hand, A2E did not directly reduce activities of a wide range of lysosomal hydrolases in in vitro assays (15). A2E can initiate apoptotic cell death in RPE and other cell types (16, 17) when present at high levels. None of the studies mentioned above measured cytoplasmic levels of A2E. In fact, at concentrations similar to those found in a...

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Hyperlipofuscinosis and Subretinal Fibrosis in Stargardtʼs Disease

Cited by 34 publications

References 0 publications

Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina

Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium

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