Lipofuscin and N-Retinylidene-N-Retinylethanolamine (A2E) Accumulate in Retinal Pigment Epithelium in Absence of Light Exposure

Boyer, Nicholas P.; Higbee, Daniel; Currin, Mark B.; Blakeley, Lorie R.; Chen, Chunhe; Ablonczy, Zsolt; Crouch, Rosalie K.; Koutalos, Yiannis

doi:10.1074/jbc.m111.329235

Cited by 115 publications

(156 citation statements)

References 44 publications

(35 reference statements)

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“…The mechanism by which ABCA4 transport activity together with chemical isomerization removes excess 11-cis-retinal from photoreceptor outer segments provides a molecular rationale for the light-independent accumulation of A2E and lipofuscin recently observed in Abca4 knockout mice (11). In the absence of ABCA4, 11-cis-retinal and its Schiff-base conjugate will accumulate in disk membranes leading to the formation of A2E and other bisretinoids in photoreceptors and lipofuscin deposits in RPE cells following phagocytosis of outer segments.…”

Section: Discussionmentioning

confidence: 96%

“…However, the light-dependent accumulation of lipofuscin and A2E in Abca4 knockout mice has been recently challenged. Boyer et al (11) have shown that the levels and rates of increase in lipofuscin, including the lipofuscin fluorophore A2E, were similar in dark-reared and cyclic light-reared Abca4 knockout mice. These results and experiments showing that the addition of 11-cis-retinal to metabolically compromised photoreceptors results in the accumulation of lipofuscin-like fluorophores have led to the suggestion that ABCA4 may play a more important role in the removal of 11-cisretinal from photoreceptor outer segments although the mechanism remains to be determined (11).…”

mentioning

confidence: 98%

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ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

Quazi

Molday

2014

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

109

101

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The visual cycle is a series of enzyme-catalyzed reactions which converts all-trans-retinal to 11-cis-retinal for the regeneration of visual pigments in rod and cone photoreceptor cells. Although essential for vision, 11-cis-retinal like all-trans-retinal is highly toxic due to its highly reactive aldehyde group and has to be detoxified by either reduction to retinol or sequestration within retinal-binding proteins. Previous studies have focused on the role of the ATP-binding cassette transporter ABCA4 associated with Stargardt macular degeneration and retinol dehydrogenases (RDH) in the clearance of all-trans-retinal from photoreceptors following photoexcitation. How rod and cone cells prevent the accumulation of 11-cis-retinal in photoreceptor disk membranes in excess of what is required for visual pigment regeneration is not known. Here we show that ABCA4 can transport N-11-cis-retinylidene-phosphatidylethanolamine (PE), the Schiff-base conjugate of 11-cis-retinal and PE, from the lumen to the cytoplasmic leaflet of disk membranes. This transport function together with chemical isomerization to its all-trans isomer and reduction to all-trans-retinol by RDH can prevent the accumulation of excess 11-cis-retinal and its Schiff-base conjugate and the formation of toxic bisretinoid compounds as found in ABCA4-deficient mice and individuals with Stargardt macular degeneration. This segment of the visual cycle in which excess 11-cis-retinal is converted to all-transretinol provides a rationale for the unusually high content of PE and its long-chain unsaturated docosahexaenoyl group in photoreceptor membranes and adds insight into the molecular mechanisms responsible for Stargardt macular degeneration.T he visual cycle plays a crucial role in the removal of all-transretinal from photoreceptor cells following photoexcitation and its conversion to 11-cis-retinal for the regeneration of visual pigments in rod and cone photoreceptor cells (1). Deficient clearance of all-trans-retinal and its Schiff-base conjugate N-retinylidenephosphatidylethanolamine (PE) from rod and cone photoreceptor outer segments results in condensation reactions which produce a mixture of bisretinoid products including the pyridinium bisretinoid compound A2PE and its hydrolytic product A2E (2, 3). These bisretinoid compounds accumulate as lipofuscin deposits in retinal pigment epithelial (RPE) cells upon phagocytosis of outer segments and have been implicated in the pathology of a number of retinal degenerative diseases. This is particularly evident in autosomal recessive Stargardt macular degeneration in which mutations in the ATP-binding cassette (ABC) transporter ABCA4 which impair the N-retinylidene-PE transport activity of ABCA4 cause a buildup of lipofuscin, atrophy of the central retina, and severe progressive loss in vision (4-8).In initial studies, Abca4 knockout mice were reported to show a light-dependent accumulation of all-trans-retinal, PE, and N-retinylidene-PE in photoreceptors and lipofuscin and A2E in RPE (9). This led to a model...

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 98%

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

Quazi

Molday

2014

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

109

101

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“…In disease marked by 11-cis-retinal deficiency, 9-cis-retinal can form iso-rhodopsin (37) and generate small light-evoked rod responses (38). The propensity for 9-cis-retinal to form cis-A2E likely explains the detection of some RPE autofluorescence in Rpe65 −/− mice (39).…”

Section: Discussionmentioning

confidence: 99%

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

Ueda

Zhao

Kim

et al. 2016

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

111

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Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE). Analysis of the bisretinoids A2E, A2-GPE, A2-dihydropyridinephosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimerphosphatidylethanolamine (all-trans-retinal dimer-PE) also decreases in albino Abca4 −/− mice reared in cyclic light compared with darkness. In albino Abca4 −/− mice receiving a diet supplemented with the antioxidant vitamin E, higher levels of RPE bisretinoid were evidenced by HPLC analysis and quantitation of fundus autofluorescence; this effect is consistent with photooxidative processes known to precede bisretinoid degradation. Amelioration of outer nuclear layer thinning indicated that vitamin E treatment protected photoreceptor cells. Conversely, in-cage exposure to short-wavelength light resulted in reduced fundus autofluorescence, decreased HPLC-quantified A2E, outer nuclear layer thinning, and increased methylglyoxal (MG)-adducted protein. MG was also released upon bisretinoid photodegradation in cells. We suggest that the lower levels of these diretinal adducts in cyclic lightreared and albino mice reflect photodegradative loss of bisretinoid. These mechanisms may underlie associations among AMD risk, oxidative mechanisms, and lifetime light exposure.bisretinoid | visual cycle | retina | retinal pigment epithelium | macular degeneration

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“…This reasoning has helped to support the hypothesis that ABCA4 functions as an exporter of all-trans-retinal. However, using ABCA4(Ϫ/Ϫ) mice, Boyer et al (25) recently showed that 11-cis-retinal can also support the formation of lipofuscin and proposed that 11-cis-retinal may be imported into the ROS discs by ABCA4. Currently, a mechanism of 11-cis-retinal import into the ROS discs is not known except through membrane diffusion.…”

mentioning

confidence: 99%

“…Based on recent studies proposing a physiological role of ABCA4 that may include translocation of 11-cis-retinal across the ROS disc membrane (25) as well as preliminary studies pointing to a specific interaction of NBD1 with 11-cis-retinal (40), we posed the following question. Do the nucleotide binding domains of ABCA4 interact with retinal, and if so, how is this interaction influenced by disease-associated mutations in these domains?…”

mentioning

confidence: 99%

Retinoid Binding Properties of Nucleotide Binding Domain 1 of the Stargardt Disease-associated ATP Binding Cassette (ABC) Transporter, ABCA4

Biswas-Fiss

Affet

et al. 2012

Journal of Biological Chemistry

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Background:The ABCA4 protein is proposed to transport all-trans-retinal from the outer segment discs of retinal rod and cone photoreceptors. Results: 11-cis-Retinal bound specifically and with high affinity to the NBD1 domain of hABCA4. Conclusion: The NBD1 domain plays further roles in addition to nucleotide hydrolysis. Significance: ABCA4 may play a novel role in the visual transduction cycle involving 11-cis-retinal.

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Lipofuscin and N-Retinylidene-N-Retinylethanolamine (A2E) Accumulate in Retinal Pigment Epithelium in Absence of Light Exposure

Cited by 115 publications

References 44 publications

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

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

Retinoid Binding Properties of Nucleotide Binding Domain 1 of the Stargardt Disease-associated ATP Binding Cassette (ABC) Transporter, ABCA4

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