A2E, a Fluorophore of RPE Lipofuscin: Can It Cause RPE Degeneration?

  • Janet R. Sparrow
  • Bolin Cai
  • Nate Fishkin
  • Young Pyo Jang
  • Sonja Krane
  • Heidi R. Vollmer
  • Jilin Zhou
  • Koji Nakanishi
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 533)

Abstract

In atrophic age-related macular degeneration (AMD) and Stargardt disease, the death of retinal pigment epithelial (RPE) cell death leads to photoreceptor cell degeneration and visual impairment. Nevertheless, the cause of RPE atrophy is poorly understood. One factor that may place RPE cells at risk is the accumulation of critical levels of lipofuscin. Indeed, several lines of evidence indicate that the excessive accumulation of lipofuscin by RPE cells is significant in terms of the etiology of AMD. Firstly, histological analyses of human donor eyes (Wing et al., 1978; Weiter et al., 1986), in addition to fundus spectrophotometry (Delori et al., 1995a; Delori et al., 2001), and confocal ophthalmoscopy (von Rückmann et al., 1997), have shown that RPE cells overlying the macula, with the exception of RPE in the cone-rich fovea, exhibit the most pronounced age-related accumulation of fluorescent material. Lipofuscin levels in RPE cells are also topographically correlated with histopathological indicators of AMD (Feeney-Burns et al., 1984; Dorey et al., 1989) and with the loss of photoreceptor cells in aged eyes (Dorey et al., 1989). Interestingly, increased fundus autofluorescence at the borders of geographic atrophy is considered to represent an enhanced accumulation of RPE lipofuscin and to implicate the latter in the disease process (Holz et al., 1999; Holz et al., 2001). While the amassing of lipofuscin by RPE is a feature of aging, excessive accretion also occurs in Stargardt disease, some forms of retinitis pigmentosa and cone-rod dystrophy (Weingeist et al., 1982; Rabb et al., 1986; Lopez et al., 1990; Delori et al., 1995b; Kennedy et al., 1995).

Keywords

Hydrolysis Electrophoresis Pyridinium Retina Adduct 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ahn J, Wong JT, Molday RS, 2000, The effect of lipid environment and retinoids on the ATPase activity of ABCR, the photoreceptor ABC transporter responsible for Stargardt macular dystrophy. JBiol Chem. 275:20399.CrossRefGoogle Scholar
  2. Allikmets R, 2000, Further evidence for an association of ABCR alleles with age-related macular degeneration. The international ABCR Screening Consortium. Am J Hum Genet. 67:487.PubMedCrossRefGoogle Scholar
  3. Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, Peiffer A, Zabriskie NA, Li Y, Hutchinson A, Dean M, Lupski JR, Leppert M, 1997, Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 277:1805.PubMedCrossRefGoogle Scholar
  4. Ben-Shabat S, Itagaki Y, Jockusch S, Sparrow JR, Turro NJ, Nakanishi K, 2002a, Formation of a nona-oxirane from A2E, a lipofuscin fluorophore related to macular degeneration, and evidence of singlet oxygen involvement. Angew Chem In! Ed. 41: 814.CrossRefGoogle Scholar
  5. Ben-Shabat S, Parish CA, Vollmer HR, Itagaki Y, Fishkin N, Nakanishi K, Sparrow JR, 2002b, Biosynthetic studies ofA2E, a major fluorophore of RPE lipofuscin. JBiol Chem. 277:7183.CrossRefGoogle Scholar
  6. Bressler SB, Bressler NM, Gragoudas ES, 2000, Age-related macular degeneration: drusen and geographic atrophy. In: Albert DM, Jakobiec FA, Azar DT, Gragoudas ES (eds) Principles and Practice of Ophthalmology, vol 3. W.B. Saunders Co, Philadelphia, pp 1982.Google Scholar
  7. Busch EM, Gorgels TGMF, Roberts JE, van Norren D, 1999a, The effects of two stereoisomers of Nacetylcysteine on photochemical damage by UVA and blue light in rat retina. Photochem Photobiol. 70:353.Google Scholar
  8. Busch EM, Gorgels TGMF, van Norren D, 19996, Temporal sequences of changes in rat retina after UV-A and blue light exposure. Vision Res. 39:1233.Google Scholar
  9. De S, Sakmar TP, 2002, Interaction of A2E with model membranes. Implications to the pathogenesis of age-related macular degeneration. JGen Physio.1120:147. CrossRefGoogle Scholar
  10. Delori FC, 1995, RPE lipofuscin in ageing and age-related macular degeneration. In: Coscas G, Piccolino FC (eds) Retinal Pigment Epithelium and Macular Disease (Documenta Ophthalmologica), vol 62. Kluwer Academic Publishers, Dordrecht, The Netherlands, pp 37.CrossRefGoogle Scholar
  11. Delori FC, Dorey CK, Staurenghi G, Arend O, Goger DG, Weiter JJ, 1995a, In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics. Invest Ophthalmol Vis Sci. 36:718.Google Scholar
  12. Delori FC, Goger DG, Dorey CK, 2001, Age-related accumulation and spatial distribution of lipofuscin in RPEGoogle Scholar
  13. of normal subjects. Invest Ophthalmol Vis Sci. 42:1855.Google Scholar
  14. Delori FC, Staurenghi G, Arend O, Dorey CK, Goger DG, Weiter JJ, 19956, In vivo measurement of lipofuscin in Stargardt’s disease--Fundus flavimaculatus. Invest Ophthalmol Vis Sci. 36:2327.Google Scholar
  15. Dorey CK, Wu G, Ebenstein D, Garsd A, Weiter JJ, 1989, Cell loss in the aging retina. Relationship to lipofuscin accumulation and macular degeneration. Invest Ophthalmol Vis Sci. 30:1691.PubMedGoogle Scholar
  16. Eldred GE, 1998 Lipofuscin and other lysosomal storage deposits in the retinal pigment epithelium. In: Marmor MF, Wolfensberger TJ (eds) The Retinal Pigment Epithelium: Function and Disease. Oxford University Press, New York, pp 651.Google Scholar
  17. Eldred GE, Katz ML, 1988, Fluorophores of the human retinal pigment epithelium: separation and spectral characterization. Exp Eye Res. 47:71.PubMedCrossRefGoogle Scholar
  18. Eldred GE, Lasky MR, 1993, Retinal age pigments generated by self-assembling lysosomotropic detergents. Nature 361:724.PubMedCrossRefGoogle Scholar
  19. Feeney-Burns L, Hilderbrand ES, Eldridge S, 1984, Aging human RPE: morphometric analysis of macular, equatorial, and peripheral cells. Invest Ophthalmol Vis Sci. 25:195.PubMedGoogle Scholar
  20. Gaillard ER, Zheng L, Merriam JC, Dillon J, 2000, Age-related changes in the absorption characteristics of the primate lens. Invest Ophthalmol Vis Sci. 41:1454.PubMedGoogle Scholar
  21. Ham WTJ, Allen RG, Feeney-Burns L, Marmor MF, Parver LM, Proctor PH, Sliney DH, Wolbarsht ML (eds), 1986, The involvement of the retinal pigment epithelium. CRC Press, Inc, Boca Raton.Google Scholar
  22. Ham WTJ, Mueller HA, Ruffolo JJJ, Millen JE, S.F. C, Guerry RK, Guerry DI, 1984, Basic mechanisms underlying the production of photochemical lesions in the mammalian retina. Curr Eye Res. 3:165.PubMedCrossRefGoogle Scholar
  23. Ham WTJ, Ruffolo JJJ, Mueller HA, Clarke AM, Moon ME, 1978, Histologic analysis of photochemical lesions produced in rhesus retina by short-wavelength light. Invest Ophthalmol Vis Sci. 17:1029.PubMedGoogle Scholar
  24. Holz FG, Bellman C, Staudt S, Schutt F, Volcker HE, 2001, Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 42:1051.PubMedGoogle Scholar
  25. Holz FG, Bellmann C, Margaritidis M, Schutt F, Otto TP, Volcker HE, 1999, Patterns of increased in vivo fundus autofluorescence in the junctional zone of geographic atrophy of the retinal pigment epithelium associated with age-related macular degeneration.Graefe’s Arch Clin Exp Ophthalmol. 237:145.CrossRefGoogle Scholar
  26. Katz ML, Drea CM, Robison WG, Jr., 1986, Relationship between dietary retinol and lipofuscin in the retinal pigment epithelium. Mech Ageing Dev. 35:291.PubMedCrossRefGoogle Scholar
  27. Katz ML, Norberg M, Stientjes HJ, 1992, Reduced phagosomal content of the retinal pigment epithelium in response to retinoid deprivatioin. Invest Ophthalmol Vis Sci. 33:2612.PubMedGoogle Scholar
  28. Katz ML, Redmond TM, 2001, Effect of Rpe65 knockouton accumulation of lipofuscin fluorophores in the retinal pigment epithelium. Invest Ophthalmol Vis Sci. 42:3023.PubMedGoogle Scholar
  29. Kennedy CJ, Rakoczy PE, Constable IJ, 1995, Lipofuscin of the retinal pigment epithelium: a review. Eye 9:763.PubMedCrossRefGoogle Scholar
  30. Kitagawa K, Nishida S, Ogura Y, 1989, In vivo quantitation of autofluorescence in human retinal pigment epithelium. Ophthalmologica 199:116.PubMedCrossRefGoogle Scholar
  31. Liu IY, White L, LaCroix AZ, 1989, The association of age-related macular degeneration and lens opacities in the aged. Am JPublic Health 79:765.CrossRefGoogle Scholar
  32. Liu J, Itagaki Y, Ben-Shabat S, Nakanishi K, Sparrow JR, 2000, The biosynthesis of A2E, a fluorophore of aging retina, involves the formation of the precursor, A2-PE, in the photoreceptor outer segment membrane. JBiol Chem. 275:29354.CrossRefGoogle Scholar
  33. Lopez PF, Maumenee IH, de la Cruz Z, Green WR, 1990, Autosomal-dominant fundus favimaculatus. Clinicopathologic correlation. Ophthalmol. 97: 798.Google Scholar
  34. Mata NL, Tzekov RT, Liu X, Weng J, Birch DG, Travis GH, 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.PubMedGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. Okubo A, Rosa RHJ, Bunce CV, Alexander RA, Fan JT, Bird AC, Luthert PJ, 1999, The relationships of age changes in retinal pigment epithelium and Bruch’s membrane. Invest Ophthalmol Vis Sci. 40:443.PubMedGoogle Scholar
  37. Parish CA, Hashimoto M, Nakanishi K, Dillon J, Sparrow JR, 1998, Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium. Proc Nail Acad Sci USA. 95:14609.CrossRefGoogle Scholar
  38. Pollack A, Bukelman A, Zalish M, Leiba H, Oliver M, 1998, The course of age-related macular degeneration following bilateral cataract surgery. Ophthalmic Surg Lasers 29:286.PubMedGoogle Scholar
  39. Pollack A, Marcovich A, Bukelman A, Oliver M, 1996, Age-related macular degeneration after extracapsular cataract extraction with intraocular lens implantation. Ophthalmology 103:1546.PubMedGoogle Scholar
  40. Putting BJ, Van Best JA, Vrensen GFJM, Oosterhuis JA, 1994, Blue-light-induced dysfunction of the blood-retinal barrier at the pigment epithelium in albino versus pigmented rabbits. Exp Eye Res 58:31.PubMedCrossRefGoogle Scholar
  41. Rabb MF, Tso MO, Fishman GA, 1986, Cone-rod dystrophy. A clinical and histopathologic report. Ophthalmology 93:1443.PubMedGoogle Scholar
  42. Ren RF, Sakai N, Nakanishi K, 1997, Total synthesis of the ocular age pigment A2E: a convergent pathway. J. Am. Chem. Soc. 119:3619.CrossRefGoogle Scholar
  43. Sakai N, Decatur J, Nakanishi K, Eldred GE, 1996, Ocular age pigment “A2E”: An unprecedented pyridinium bisretinoid. J. Am. Chem. Soc. 118:1559.CrossRefGoogle Scholar
  44. Schutt F, Davies S, Kopitz J, Holz FG, Boulton ME, 2000, Photodamage to human RPE cells by A2-E, a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci. 41:2303.PubMedGoogle Scholar
  45. Sparrow JR, Cai B, 2001, Blue light-induced apoptosis of A2E-containing RPE: involvement of caspase-3 and protection by Bel-2. Invest Ophthalmol Vis Sci 42:1356.PubMedGoogle Scholar
  46. 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.PubMedGoogle Scholar
  47. Sparrow JR, Parish CA, Hashimoto M, Nakanishi K, 1999, A2E, a lipofuscin fluorophore, in human retinal pigmented epithelial cells in culture. Invest Ophthalmol Vis Sci 40:2988.PubMedGoogle Scholar
  48. Sparrow JR, Zhou J, Ben-Shabat S, Vollmer H, Itagaki Y, Nakanishi K, 2002, Involvement of oxidative mechanisms in blue light induced damage to A2E-laden RPE. Invest Ophthalmol Vis Sci. 43: 222.Google Scholar
  49. Sparrow Jr, Zhou J, Cai B, 2003, DNA is a target of the photodynamic effects elicited in A2E-laden RPE by blue light illumination. IOVS (in press) Google Scholar
  50. Sun H, Molday RS, Nathans J, 1999, Retinal stimulates ATP hydrolysis by purified and reconstituted ABCR, the photoreceptor-specific ATP-binding cassette transporter responsible for Stargardt disease. J Biol Chem. 274:8269.PubMedCrossRefGoogle Scholar
  51. Taylor HR, West S, Munoz B, Rosenthal FS, Bressler SB, Bressler NM, 1992, The long-term effects of visible light on the eye [see comments]. Arch Ophthalmol 110:99.PubMedCrossRefGoogle Scholar
  52. von Rückmann A, Fitzke FW, Bird AC, 1997, Fundus autofluorescence in age-related macular disease imaged with a laser scanning ophthalmoscope. Invest Ophthalmol Vis Sci. 38:478.Google Scholar
  53. Weingeist TA, Kobrin JL, Watzke RC, 1982, Histopathology of Best’s macular dystrophy. Arch Ophthalmol. 100:1108.PubMedCrossRefGoogle Scholar
  54. Weiter JJ, Delori FC, Wing GL, Fitch KA, 1986, Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes. Invest Ophthalmol Vis Sci. 27:145.PubMedGoogle Scholar
  55. Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG, Travis GH, 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.PubMedCrossRefGoogle Scholar
  56. West SK, Rosenthal FS, Bressler NM, Bressler SB, Munoz B, Fine SL, Taylor HR, 1989, Exposure to sunlight and other risk factors for age-related macular degeneration [see comments]. Arch Ophthalmol 107: 875PubMedCrossRefGoogle Scholar
  57. Wing GL, Blanchard GC, Weiter JJ, 1978, The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium. Invest Ophthalmol Vis Sci. 17:601.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Janet R. Sparrow
  • Bolin Cai
  • Nate Fishkin
  • Young Pyo Jang
  • Sonja Krane
  • Heidi R. Vollmer
  • Jilin Zhou
  • Koji Nakanishi
    • 1
  1. 1.Departments of Ophthalmology and ChemistryColumbia UniversityNew YorkUSA

Personalised recommendations