The DOI matches its Crossref record; 56 of the 59 references it cites were found in a registry or an index.
Lipofuscin and N-Retinylidene-N-Retinylethanolamine (A2E) Accumulate in Retinal Pigment Epithelium in Absence of Light Exposure
Open accessAbstract
The age-dependent accumulation of lipofuscin in the retinal pigment epithelium (RPE) has been associated with the development of retinal diseases, particularly age-related macular degeneration and Stargardt disease. A major component of lipofuscin is the bis-retinoid N-retinylidene-N-retinylethanolamine (A2E). The current model for the formation of A2E requires photoactivation of rhodopsin and subsequent release of all-trans-retinal. To understand the role of light exposure in the accumulation of lipofuscin and A2E, we analyzed RPEs and isolated rod photoreceptors from mice of different ages and strains, reared either in darkness or cyclic light. Lipofuscin levels were determined by fluorescence imaging, whereas A2E levels were quantified by HPLC and UV-visible absorption spectroscopy. The identity of A2E was confirmed by tandem mass spectrometry. Lipofuscin and A2E levels in the RPE increased with age and more so in the Stargardt model Abca4(-/-) than in the wild type strains 129/sv and C57Bl/6. For each strain, the levels of lipofuscin precursor fluorophores in dark-adapted rods and the levels and rates of increase of RPE lipofuscin and A2E were not different between dark-reared and cyclic light-reared animals. Both 11-cis- and all-trans-retinal generated lipofuscin-like fluorophores when added to metabolically compromised rod outer segments; however, it was only 11-cis-retinal that generated such fluorophores when added to metabolically intact rods. The results suggest tha…
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Immunohistology showed RPE65 to be present in the OS of these cone-like photoreceptors (Figure 6, B-C) (Boyer et al., 2012b).”
From New insights into retinoid metabolism and cycling within the retina (2013) · cites this paper as Boyer et al., 2012b
In the citing paper
“Furthermore, direct addition of 11-cis retinal to rod photoreceptors results in the generation of lipofuscin precursors in the absence of light.”
From New insights into retinoid metabolism and cycling within the retina (2013) · cites this paper as Boyer et al., 2012a
In the citing paper
“While it is clear that retinoids are involved in lipofuscin, recent evidence shows 11-cis retinal itself may be a major source of lipofuscin and A2E (Boyer et al., 2012a).”
From New insights into retinoid metabolism and cycling within the retina (2013) · cites this paper as Boyer et al., 2012a
In the citing paper
“These results are based on the finding that mice raised in the dark have the same levels of lipofuscin and lipofuscin precursors as animals raised in cyclic light.”
From New insights into retinoid metabolism and cycling within the retina (2013) · cites this paper as Boyer et al., 2012a
Citations
Cites
The Human ATP-Binding Cassette (ABC) Transporter SuperfamilyPreprint
Dean, M. C., Rzhetsky, A., & Allikmets, R. L. (2001) · Genome Research · doi:10.1101/gr.184901 · Cited by 1,820
Allikmets, R., Singh, N., Sun, H., Shroyer, N. F., Hutchinson, A., Chidambaram, A., Gerrard, B., Baird, L., Stauffer, D., Peiffer, A., et al. (1997) · Nature Genetics · doi:10.1038/ng0397-236 · Cited by 1,435 · cited 5×
“As such, deficiencies in ABCA4 function would lead to an accumulation in N-retinylidene-PE, driving the formation of the precursors of A2E and lipofuscin after photoactivation of rhodopsin.”
BackgroundInfluentialThe renewal of photoreceptor cell outer segments
Young, R. W. (1967) · The Journal of Cell Biology · doi:10.1083/jcb.33.1.61 · Cited by 1,184 · cited 1×
“Keeping in mind that 10% ofmouse rod outer segments is being phagocytosed daily by theRPE (46), comparison of the amounts ofA2E found in the retina and the accumulated amounts in the RPE would indicate that A2E and probably other lipofuscin precursors be eliminated even in dark-reared animals.”
BackgroundDelori, F. C., Dorey, C. K., Staurenghi, G., Arend, O., Goger, D. G., & Weiter, J. J. (1995) · PubMed · Cited by 938
Weng, J., Mata, N. L., Azarian, S. M., Tzekov, R. T., Birch, D. G., & Travis, G. H. (1999) · Cell · doi:10.1016/s0092-8674(00)80602-9 · Cited by 881 · cited 6×
“Mice that lack Abca4 exhibit a large increase in RPE lipofuscin and bis-retinoid, including A2E, accumulation (17, 20, 21).”
BackgroundResultInfluentialRPE lipofuscin and its role in retinal pathobiology
Sparrow, J. R., & Boulton, M. (2005) · Experimental Eye Research · doi:10.1016/j.exer.2005.01.007 · Cited by 644
Sparrow, J. R., Nakanishi, K., & Parish, C. A. (2000) · PubMed · Cited by 566
Oxidative Damage and Age Related Macular Degeneration
Renganathan, K. (2008) · OhioLink ETD Center (Ohio Library and Information Network) · Cited by 566
(1999) · PubMed · Cited by 539
ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine.
Hamon, Y., Broccardo, C., Chambenoit, O., Luciani, M., Toti, F., Chaslin, S., Freyssinet, J., Devaux, P. F., McNeish, J. D., Marguet, D., et al. (2000) · Nature Cell Biology · doi:10.1038/35017029 · Cited by 529
Retinal age pigments generated by self-assembling lysosomotropic detergents
Eldred, G., & Lasky, M. R. (1993) · Nature · doi:10.1038/361724a0 · Cited by 489
Parish, C. A., Hashimoto, M., Nakanishi, K., Dillon, J., & Sparrow, J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14609 · Cited by 474
Mata, N. L., Weng, J., & Travis, G. H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.130110497 · Cited by 456
Terman, A., & Brunk, U. T. (2004) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2003.08.009 · Cited by 451
Ebrey, T. G., & Koutalos, Y. (2001) · Progress in Retinal and Eye Research · doi:10.1016/s1350-9462(00)00014-8 · Cited by 441
Self-citationAge-related accumulation and spatial distribution of lipofuscin in RPE of normal subjects.
Delori, F. C., Goger, D. G., & Dorey, C. K. (2001) · PubMed · Cited by 424
Photolyzed rhodopsin catalyzes the exchange of GTP for bound GDP in retinal rod outer segments.
Fung, B. K.-K., & Stryer, L. (1980) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.77.5.2500 · Cited by 397
The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium.
Wing, G. L., Blanchard, G. C., & Weiter, J. J. (1978) · PubMed · Cited by 394
Feeney, L. (1978) · PubMed · Cited by 389
Sun, H., Molday, R. S., & Nathans, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.12.8269 · Cited by 353
A2E, a lipofuscin fluorophore, in human retinal pigmented epithelial cells in culture.
Sparrow, J. R., Parish, C. A., Hashimoto, M., & Nakanishi, K. (1999) · PubMed · Cited by 310
Wenzel, A., Remé, C. E., Williams, T. P., Hafezi, F., & Grimm, C. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-01-00053.2001 · Cited by 291
PARTICIPATION OF THE RETINAL PIGMENT EPITHELIUM IN THE ROD OUTER SEGMENT RENEWAL PROCESS
Young, R. W., & Bok, D. (1969) · Journal of Cell Biology · doi:10.1083/jcb.42.2.392 · Cited by 271
Liu, J., Itagaki, Y., Ben-Shabat, S., Nakanishi, K., & Sparrow, J. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m910191199 · Cited by 255
In vivo measurement of lipofuscin in Stargardt's disease--Fundus flavimaculatus.
Delori, F. C., Staurenghi, G., Arend, O., Dorey, C. K., Goger, D. G., & Weiter, J. J. (1995) · PubMed · Cited by 245
Chen, Y., Okano, K., Maeda, T., Chauhan, V., Golczak, M., Maeda, A., & Palczewski, K. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.315432 · Cited by 229
Blue Light-Induced Singlet Oxygen Generation by Retinal Lipofuscin in Non-Polar Media
Rôżanowska, M., Wessels, J. M., Boulton, M. E., Burke, J. M., Rodgers, M. A. J., Truscott, T. G., & Sarna, T. (1998) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(97)00395-x · Cited by 227
Mata, N. L., Tzekov, R. T., Liu, X., Weng, J., Birch, D. G., & Travis, G. H. (2001) · PubMed · Cited by 219
Biosynthetic Studies of A2E, a Major Fluorophore of Retinal Pigment Epithelial Lipofuscin
Ben-Shabat, S., Parish, C. A., Vollmer, H. R., Itagaki, Y., Fishkin, N., Nakanishi, K., & Sparrow, J. R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m108981200 · Cited by 214
Wang, N., Lan, D., Gerbod-Giannone, M. C., Linsel‐Nitschke, P., Jehle, A. W., Chen, W., Martinez, L. O., & Tall, A. R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307831200 · Cited by 205
Circadian nature of rod outer segment disc shedding in the rat.
LaVail, M. M. (1980) · PubMed · Cited by 199
Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration
Stone, E. M., Webster, A. R., Vandenburgh, K., Streb, L. M., Hockey, R. R., Lotery, A. J., & Sheffield, V. C. (1998) · Nature Genetics · doi:10.1038/3798 · Cited by 197
Phospholipid meets all-trans-retinal: the making of RPE bisretinoids
Sparrow, J. R., Wu, Y., Kim, C. Y., & Zhou, J. (2010) · Journal of Lipid Research · doi:10.1194/jlr.r000687 · Cited by 193
Molday, R. S., Zhong, M., & Quazi, F. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.02.004 · Cited by 182
Beharry, S., Zhong, M., & Molday, R. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405216200 · Cited by 174
Rod Outer Segment Retinol Dehydrogenase: Substrate Specificity and Role in Phototransduction
Palczewski, K., Jäger, S., Buczyłko, J., Crouch, R. K., Bredberg, D. L., Hofmann, K. P., Asson–Batres, M. A., & Saari, J. C. (1994) · Biochemistry · doi:10.1021/bi00250a027 · Cited by 173
Self-citationRetinal Pigment Epithelium Lipofuscin Proteomics
Ng, K.-P., Gugiu, B., Renganathan, K., Davies, M. W., Gu, X., Crabb, J. S., Kim, S. R., Różanowska, M. B., Bonilha, V. L., Rayborn, M. E., et al. (2008) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m700525-mcp200 · Cited by 162
Wu, Y., Yanase, E., Feng, X., Siegel, M. M., & Sparrow, J. R. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0913112107 · Cited by 152
Influence of early photoreceptor degeneration on lipofuscin in the retinal pigment epithelium
Katz, M. L., Drea, C. M., Eldred, G. E., Hess, H. H., & Robison, W. G. (1986) · Experimental Eye Research · doi:10.1016/s0014-4835(86)80023-9 · Cited by 149
Kim, S. R., Jang, Y. P., Jockusch, S., Fishkin, N. E., Turro, N. J., & Sparrow, J. R. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708714104 · Cited by 145
(2001) · PubMed · Cited by 136
Katz, M. L., & Robison, W. G. (2002) · Archives of Gerontology and Geriatrics · doi:10.1016/s0167-4943(02)00005-5 · Cited by 122
Limited Roles of Rdh8, Rdh12, and Abca4 in all- trans -Retinal Clearance in Mouse Retina
Maeda, A., Golczak, M., Maeda, T., & Palczewski, K. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.09-3944 · Cited by 94
Katz, M. L. (1996) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(96)01817-9 · Cited by 77
Retinal light damage reduces autofluorescent pigment deposition in the retinal pigment epithelium.
Katz, M. L., & Eldred, G. E. (1989) · PubMed · Cited by 63
Lyubarsky, A., Savchenko, A. B., Morocco, S. B., Daniele, L. L., Redmond, T. M., & Pugh, E. N. (2005) · Biochemistry · doi:10.1021/bi0505363 · Cited by 63
Spatial localization of A2E in the retinal pigment epithelium
Grey, A. C., Crouch, R. K., Koutalos, Y., Schey, K. L., & Ablonczy, Z. (2011) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.10-7020 · Cited by 52
Self-citationBui, T. V., Han, Y., Radu, R. A., Travis, G. H., & Mata, N. L. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601380200 · Cited by 48
Photooxidation of RPE lipofuscin bisretinoids enhances fluorescence intensity
Kim, S. R., Jang, Y. P., & Sparrow, J. R. (2009) · Vision Research · doi:10.1016/j.visres.2009.09.015 · Cited by 37
Characterization of phospholipase D activity in bovine photoreceptor membranes
Salvador, G. A., & Giusto, N. M. (1998) · Lipids · doi:10.1007/s11745-998-0281-z · Cited by 34
Formation of all- trans Retinol after Visual Pigment Bleaching in Mouse Photoreceptors
Chen, C., Blakeley, L. R., & Koutalos, Y. (2009) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.08-3336 · Cited by 34
Self-citationBlakeley, L. R., Chen, C.-K., Chen, C.-K., Chen, J., Crouch, R. K., Travis, G. H., & Koutalos, Y. (2011) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.10-6694 · Cited by 23
Self-citationMass spectrometry provides accurate and sensitive quantitation of A2E
Gutierrez, D. B., Blakeley, L. R., Goletz, P. W., Schey, K. L., Hanneken, A. M., Koutalos, Y., Crouch, R. K., & Ablonczy, Z. (2010) · Photochemical & Photobiological Sciences · doi:10.1039/c0pp00230e · Cited by 23
Self-citationLipofuscin and A2E Accumulate with Age in the Retinal Pigment Epithelium of Nrl−/− Mice†
Boyer, N. P., Tang, P. H., Higbee, D., Ablonczy, Z., Crouch, R. K., & Koutalos, Y. (2012) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.2012.01127.x · Cited by 14
Self-citationChen, C., & Koutalos, Y. (2010) · Photochemical & Photobiological Sciences · doi:10.1039/c0pp00124d · Cited by 10
Self-citationBoyer, N. P., Higbee, D., Ablonczy, Z., Crouch, R. K., & Koutalos, Y. (2012) · Investigative Ophthalmology & Visual Science · Cited by 1
Self-citation
Cited by
Sorted by citations
Functions, Therapeutic Applications, and Synthesis of Retinoids and Carotenoids
Álvarez, R., Vaz, B., Gronemeyer, H., & de Lera, Á. R. (2014) · Chemical Reviews · doi:10.1021/cr400126u · Cited by 260
Molday, R. S., & Moritz, O. L. (2015) · Journal of Cell Science · doi:10.1242/jcs.175687 · Cited by 235
Senescence in the pathogenesis of age-related macular degeneration
Blasiak, J. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03420-x · Cited by 183
Quantitative Fundus Autofluorescence in Healthy Eyes
Greenberg, J. P., Duncker, T., Woods, R. L., Smith, R. T., Sparrow, J. R., & Delori, F. C. (2013) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.13-12445 · Cited by 168
Lenis, T. L., Hu, J., Ng, S. Y., Jiang, Z., Sarfare, S., Lloyd, M. B., Esposito, N. J., Samuel, W., Jaworski, C., Bok, D., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1802519115 · Cited by 158
Metadata
- Authors
- Boyer, N. P., Higbee, D., Currin, M. B., Blakeley, L. R., Chen, C., Ablonczy, Z., Crouch, R. K., & Koutalos, Y.
- Affiliations
- Medical University of South Carolina (US)
- Corresponding author
- Koutalos, Yiannis
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 287
- Issue
- 26
- Pages
- 22276-22286
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3381188
- OpenAlex
- W1984815704
- Cited by
- 133
- References
- 59
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 4 · 2023: 10 · 2022: 7 · 2021: 9 · 2020: 18 · 2019: 2 · 2018: 10 · 2017: 11 · 2016: 6 · 2015: 15 · 2014: 12 · 2013: 10 · 2012: 6
- FWCI
- 12.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1c06rr015455-01a1)
- National Eye Institute (R01EY019065, EY014850, R01EY014850, EY-014793, R24EY014793, R21EY020661, EY-004939, EY020661, R01EY004939)
- National Center for Research Resources (C06 RR-015455)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- lipofuscin, A2E, retinal pigment epithelium, rod photoreceptors, light exposure, aging, ABCA4, Stargardt disease, age-related macular degeneration, 11-cis-retinal, all-trans-retinal, rhodopsin regeneration, dark rearing
- MeSH terms
- Animals, Chromatography, High Pressure Liquid, Color, Light, Lipofuscin, Macular Degeneration, Mice, Inbred C57BL, Microscopy, Fluorescence, Models, Biological, Retina, Retinaldehyde, Retinoids, Rod Cell Outer Segment, ATP-Binding Cassette Transporters, Mice, Retinal Pigment Epithelium
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
