Lipofuscin Fluorophore Inhibits Lysosomal Protein Degradation and May Cause Early Stages of Macular Degeneration

Eldred, Graig E.

doi:10.1159/000213722

Cited by 78 publications

(51 citation statements)

References 40 publications

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“…The ABCR protein moves bleached retinoid across the rod disk membrane (49). In the AbcrϪ͞Ϫ mouse, bleached chromophore couples with ethanolamine to form lipofuscin (50), which accumulate in the RPE (51), and in human, this leads to vision loss in Stargardt macular degeneration (52). As dark rearing of AbcrϪ͞Ϫ mice prolongs rod cell survival, presumably by decreasing the retinoid turnover, a possible therapeutic strategy would be to slow production of 11-cis retinal and thereby limit isomerization events.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy

Sieving¹

2001

Proceedings of the National Academy of Sciences

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As rod photoreceptors are responsible for night vision, we administered isotretinoin to rats to learn whether night blindness resulted from rod cell death or from rod functional impairment. High-dose isotretinoin was given daily for 2 months and produced systemic toxicity, but this caused no histological loss of rod photoreceptors, and rod-driven electroretinogram amplitudes were normal after prolonged dark adaptation. Additional studies showed, however, that even a single dose of isotretinoin slowed the recovery of rod signaling after exposure to an intense bleaching light, and that rhodopsin regeneration was markedly slowed. When only a single dose was given, rod function recovered to normal within several days. Rods and cones both showed slow recovery from bleach after isotretinoin in rats and in mice. HPLC analysis of ocular retinoids after isotretinoin and an intense bleach showed decreased levels of rhodopsin chromophore, 11-cis retinal, and the accumulation of the biosynthetic intermediates, 11-cis and all-trans retinyl esters. Isotretinoin was also found to protect rat photoreceptors from light-induced damage, suggesting that strategies of altering retinoid cycling may have therapeutic implications for some forms of retinal and macular degeneration.vitamin A ͉ rhodopsin ͉ rat ͉ electroretinogram ͉ rod photoreceptor V isual response in vertebrate rod photoreceptors begins when light isomerizes the rhodopsin chromophore 11-cis retinal to all-trans retinal. The bleached photopigment activates the signal transduction cascade within the rod, leading to membrane hyperpolarization and thereby to retinal visual signaling. Part of the recovery mechanism from bleach requires reconversion of the chromophore to 11-cis retinal by enzymatic reactions (the vitamin A cycle) that occur within the adjacent retinal pigment epithelium (RPE) (1). Disruption of the vitamin A cycle retards restoration of night vision sensitivity. Human dietary vitamin A deficiency can cause night blindness (2), as does dietary substitution of retinoic acid in rats (3). Alternatively, night blindness can result from death and loss of rod photoreceptors in retinal degeneration (4), including some forms involving mutations in genes necessary for retinoid processing in the RPE (5). Some isotretinoin patients report impaired visual sensitivity at night and daytime glare sensitivity, suggesting photoreceptor compromise or loss (6). We have investigated the mechanism of isotretinoin-induced night blindness by evaluating ERGs, rates of rhodopsin regeneration, and retinoid processing in rats. We also evaluated the possible therapeutic benefit of isotretinoin in the rat light-damage model of retinal degeneration. Materials and MethodsAnimals. Protocols were approved by the University of Michigan's Committee on the Use and Care of Animals. SpragueDawley male 7-wk-old albino rats (Charles River Breeding Laboratories) were housed in 12:12 h light͞dark cycle of 5 lux fluorescent white light. Rats were fed high-fat breeding chow (Formulab; PMI Feeds, St. Lou...

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Section: Discussionmentioning

confidence: 99%

Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy

Sieving¹

2001

Proceedings of the National Academy of Sciences

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“…Nevertheless, the mechanism of production of A2E has not been demonstrated. Similarly, the site of its formation, whether within phagolysosomal compartments of the RPE cell (7,8) or within the photoreceptor outer segment membrane before phagocytosis, remains unknown. We have previously proposed that the biogenesis of A2E is initiated by the formation of a Schiff base between all-trans-retinal and PE to create a PE-all-trans-retinal Schiff base adduct (4).…”

mentioning

confidence: 99%

The Biosynthesis of A2E, a Fluorophore of Aging Retina, Involves the Formation of the Precursor, A2-PE, in the Photoreceptor Outer Segment Membrane

Liu

Itagaki

Ben‐Shabat

et al. 2000

Journal of Biological Chemistry

235

204

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The autofluorescent lipofuscin that accumulates in retinal pigment epithelial cells with age may contribute to an age-related decline in cell function. The major lipofuscin fluorophore, A2E, is a pyridinium bisretinoid. We previously proposed that the biogenesis of A2E involves the following: (i) formation of the Schiff base, N-retinylidene phosphatidylethanolamine from alltrans-retinal and phosphatidylethanolamine in the photoreceptor outer segment membrane; (ii) further reaction of N-retinylidene phosphatidylethanolamine with retinal to yield phosphatidylethanolamine-bisretinoid, A2-PE; (iii) hydrolysis of A2-PE to generate A2E. To provide evidence for this biogenic scheme, all-trans-retinal was reacted with dipalmitoyl-L-␣-phosphatidylethanolamine to yield DP-A2-PE (A2-PE), as confirmed by UV, with mass spectrometry revealing the molecular ion at m/z 1222.9 (C 77 H 124 O 8 PN) accompanied by product ion at m/z 672.8, representing the phosphoryl-A2E fragment of A2-PE. In reaction mixtures of retinal and outer segments and in samples of Royal College of Surgeons rat retina containing outer segment membranous debris, A2-PE was detected as a series of high performance liquid chromatography peaks, each with UV similar to reference A2-PE. By mass spectrometry, A2-PE consisted of multiple peaks, representing fatty acids with different chain lengths, and the phosphoryl-A2E moiety, m/z 673. Incubation of the retinal/outer segment reaction mixture with phospholipase D generated A2E, as detected by high performance liquid chromatography, thus confirming A2-PE as the A2E precursor.The lipofuscin that accumulates in retinal pigmented epithelial (RPE) 1 cells with age and in some retinal disorders is a complex mixture of fluorophores, some elements of which are derived from molecular components of the photoreceptor cell membrane. These membrane elements become deposited in the RPE cell as a result of the latter's role in phagocytosing packets of outer segment membrane that are shed by the photoreceptor cell during the daily process of membrane renewal. It is now known that a major hydrophobic constituent of RPE lipofuscin is the fluorophore, A2E (1), a pyridinium bisretinoid (2, 3). A2E has been quantified in human donor eyes, and a photoisomer of A2E, iso-A2E, has been characterized (4). For many years, the impact of lipofuscin accumulation on the RPE cell has been poorly understood. Recently, however, we have demonstrated that when A2E is accumulated to critical concentrations by cultured RPE, it can manifest detergent-like activity (5) and can serve as an initiator of blue light-induced cellular damage (6). A2E is generated from all-trans-retinal and ethanolamine, the former being released from photoactivated rhodopsin, and the latter being the head group of phosphatidylethanolamine (PE), an abundant membrane phospholipid (1-3). Nevertheless, the mechanism of production of A2E has not been demonstrated. Similarly, the site of its formation, whether within phagolysosomal compartments of the RPE cell (7,8) or within the p...

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“…Two molecules of all-trans-retinal ) react with ethanolamine in oxidative conditions to produce A2E (Suter et al 2000), which accumulates in the RPE with age (Eldred 1995). A2E appeared to induce RPE toxicity by suppressing lysosomal function, suggesting visual cycle byproducts may contribute to AMD pathology (Suter et al 2000).…”

Section: Visual Cycle Modulatorsmentioning

confidence: 99%

“…A2E appeared to induce RPE toxicity by suppressing lysosomal function, suggesting visual cycle byproducts may contribute to AMD pathology (Suter et al 2000). Because A2E is toxic to RPE and was thought to be a principal component of the autofluorescent material lipofuscin that appears in many AMD patients (Eldred 1995), several groups attempted to create therapeutics that could halt its formation and slow AMD progression. Given the well-defined functional and biochemical role of the visual cycle protein RPE-specific protein 65 kDa (RPE65) , inhibitors specific to RPE65 were developed to slow the rate of retinoid metabolism to slow A2E generation (Buschini et al 2015;Zhang et al 2015).…”

Section: Visual Cycle Modulatorsmentioning

confidence: 99%

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

Narayanan

Kuppermann

2016

Handbook of Experimental Pharmacology

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Lipofuscin Fluorophore Inhibits Lysosomal Protein Degradation and May Cause Early Stages of Macular Degeneration

Cited by 78 publications

References 40 publications

Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy

Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy

The Biosynthesis of A2E, a Fluorophore of Aging Retina, Involves the Formation of the Precursor, A2-PE, in the Photoreceptor Outer Segment Membrane

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

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