Abstract
Vitamin A aldehyde-derived compounds accumulate in retinal pigment epithelial (RPE) cells as bisretinoid lipofuscin pigments and have been linked to some retinal disorders, including recessive ABCA4-related disease, dominant ELOVL-4-related maculopathy, retinal degeneration caused by mutations in the Best-1 gene, and age-related macular degeneration. These bisretinoid compounds are likely unique to RPE cells. A2E is the best known but is not the only bisretinoid constituent of RPE lipofuscin; the others include all-trans-retinal dimer, all-trans-retinal dimer-PE, all-trans-retinal dimer-E, and A2-dihydropyridine-phosphatidylethanolamine (A2-DHP-PE). Isomers and photooxidized forms of these compounds are further additions to this mixture and all are constituents of human RPE lipofuscin.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Ben-Shabat S, Itagaki Y, Jockusch S et al (2002a) Formation of a nona-oxirane from A2E, a lipofuscin fluorophore related to macular degeneration, and evidence of singlet oxygen involvement. Angew Chem Int Ed 41:814–817
Ben-Shabat S, Parish CA, Vollmer HR et al (2002b) Biosynthetic studies of A2E, a major fluorophore of RPE lipofuscin. J Biol Chem 277:7183–7190
Boulton M, Docchio F, Dayhaw-Barker P et al (1990) Age-related changes in the morphology, absorption and fluorescence of melanosomes and lipofuscin granules of the retinal pigment epithelium. Vision Res 30:1291–1303
Clancy CMR, Krogmeier JR, Pawlak A et al (2000) Atomic force microscopy and near-field scanning optical microscopy measurements of single human retinal lipofuscin granules. J Phys Chem B 104:12098–12101
Crabb JW, Miyagi M, Gu X et al (2002) Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci USA 99:14682–14687
Cuervo AM, Dice JR (2000) When lysosomes get old. Exp Gerontol 35:119–131
Feeney-Burns L, Eldred GE (1983) The fate of the phagosome: conversion to ‘age pigment’ and impact in human retinal pigment epithelium. Trans Ophthalmol Soc UK 103:416–421
Fishkin N, Sparrow JR, Allikmets R et al (2005) Isolation and characterization of a retinal pigment epithelial cell fluorophore: an all-trans-retinal dimer conjugate. Proc Natl Acad Sci USA 102:7091–7096
Handa JT, Verzijl N, Matsunaga H et al (1999) Increase in advanced glycation end product pentosidine in Bruch’s membrane with age. Invest Ophthalmol Vis Sci 40:775–779
Haralampus-Grynaviski NM, Lamb LE, Clancy CMR et al (2003) Spectroscopic and morphological studies of human retinal lipofuscin granules. Proc Natl Acad Sci USA 100:3179–3184
Jang YP, Matsuda H, Itagaki Y et al (2005) Characterization of peroxy-A2E and furan-A2E photooxidation products and detection in human and mouse retinal pigment epithelial cells lipofuscin. J Biol Chem 280:39732–39739
Katz ML, Drea CM, Eldred GE et al (1986) Influence of early photoreceptor degeneration on lipofuscin in the retinal pigment epithelium. Exp Eye Res 43:561–573
Kim SR, Jockusch S, Itagaki Y et al (2008) Mechanisms involved in A2E oxidation. Exp Eye Res 86:975–982
Kim SR, Fishkin N, Kong J et al (2004) The Rpe65 Leu450Met variant is associated with reduced levels of the RPE lipofuscin fluorophores A2E and iso-A2E. Proc Natl Acad Sci USA 101:11668–11672
Kim SR, Jang YP, Jockusch S et al (2007) The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model. Proc Natl Acad Sci USA 104:19273–19278
Kuny S, Gaillard F, Mema SC et al (2010) Inner Retina Remodeling in a Mouse Model of Stargardt-like Macular Dystrophy (STGD3). Invest Ophthalmol Vis Sci 51:2248–2262
Maiti P, Kong J, Kim SR et al (2006) Small molecule RPE65 antagonists limit the visual cycle and prevent lipofuscin formation. Biochem 45:852–860
Mata NL, Weng J, Travis GH (2000) Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci USA 97:7154–7159
Mata NL, Tzekov RT, Liu X et al (2001) Delayed dark adaptation and lipofuscin accumulation in abcr+/− mice: implications for involvement of ABCR in age-related macular degeneration. Invest Ophthalmol Vis Sci 42:1685–1690
Ng KP, Gugiu BG, Renganathan K et al (2008) Retinal pigment epithelium lipofuscin proteomics. Mol Cell Proteomics 7:1397–1405
Parish CA, Hashimoto M, Nakanishi K et al (1998) Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium. Proc Natl Acad Sci USA 95:14609–14613
Sakai N, Decatur J, Nakanishi K et al (1996) Ocular age pigment “A2E”: An unprecedented pyridinium bisretinoid. J Am Chem Soc 118:1559–1560
Sparrow JR (2007) RPE lipofuscin: formation, properties and relevance to retinal degeneration. In: Tombran-Tink J, Barnstable CJ (eds) Retinal Degenerations: Biology, Diagnostics and Therapeutics. Humana Press, Totowa, NJ
Sparrow JR, Boulton M (2005) RPE lipofuscin and its role in retinal photobiology. Exp Eye Res 80:595–606
Sparrow JR, Nakanishi K, Parish CA (2000) The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Invest Ophthalmol Vis Sci 41:1981–1989
Sparrow JR, Kim SR, Cuervo AM et al (2008) A2E, a pigment of RPE lipofuscin is generated from the precursor A2PE by a lysosomal enzyme activity. Adv Exp Med and Biol 613:393–398
Sparrow JR, Zhou J, Ben-Shabat S et al (2002) Involvement of oxidative mechanisms in blue light induced damage to A2E-laden RPE. Invest Ophthalmol Vis Sci 43:1222–1227
Sparrow JR, Wu Y, Nagasaki T et al (2010) Fundus autofluorescence and the bisretinoids of retina. Photochem Photobiol Sci 9:1480–1489
Vasireddy V, Jablonski MM, Khan NW et al (2009) Elovl4 5-bp deletion knock-in mouse model for Stargardt-like macular degeneration demonstrates accumulation of ELOVL4 and lipofusin. Exp Eye Res 89:905–912
Weng J, Mata NL, Azarian SM et al (1999) Insights into the function of Rim protein in photoreceptors and etiology of Stargardt’s disease from the phenotype in abcr knockout mice. Cell 98:13–23
Wu L, Nagasaki T, Sparrow JR (2010a) Photoreceptor cell degeneration in Abcr −/− mice. Adv Exp Med Biol 664:533–539
Wu Y, Fishkin NE, Pande A et al (2009) Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease. J Biol Chem 284:20155–20166
Wu Y, Yanase E, Feng X et al (2010b) Structural characterization of bisretinoid A2E photocleavage products and implications for age-related macular degeneration. Proc Natl Acad Sci USA 107:7275–7280
Yin D (1996) Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores. Free Rad Biol Med 21:871–888
Acknowledgments
This work was supported by National Institutes of Health Grant EY12951 (to JRS) and a grant from Research to Prevent Blindness to the Department of Ophthalmology. JRS is the recipient of a Research to Prevent Blindness Senior Investigator Award.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2012 Springer Science+Business Media, LLC
About this paper
Cite this paper
Sparrow, J.R., Yamamoto, K. (2012). The Bisretinoids of RPE Lipofuscin: A Complex Mixture. In: LaVail, M., Ash, J., Anderson, R., Hollyfield, J., Grimm, C. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 723. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-0631-0_97
Download citation
DOI: https://doi.org/10.1007/978-1-4614-0631-0_97
Published:
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4614-0630-3
Online ISBN: 978-1-4614-0631-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)