The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model.
The bis-retinoid pigments that accumulate in retinal pigment epithelial cells as lipofuscin are associated with inherited and age-related retinal disease. In addition to A2E and related cis isomers, we previously showed that condensation of two molecules of all-trans-retinal leads to the formation of a protonated Schiff base conjugate, all-trans-retinal dimer-phosphatidylethanolamine. Here we report the characterization of the related pigments, all-trans-retinal dimer-ethanolamine and unconjugated all-trans-retinal dimer, in human and mouse retinal pigment epithelium. In eyecups of Abcr(-/-) mice, a model of recessive Stargardt macular degeneration, all-trans-retinal dimer-phosphatidylethanolamine was increased relative to wild type and was more abundant than A2E. Total pigment of the all-trans-retinal dimer series (sum of all-trans-retinal dimer-phosphatidylethanolamine, all-trans-retinal dimer-ethanolamine, and all-trans-retinal dimer) increased with age in Abcr(-/-) mice and was modulated by amino acid variants in Rpe65. In in vitro assays, enzyme-mediated hydrolysis of all-trans-retinal dimer-phosphatidylethanolamine generated all-trans-retinal dimer-ethanolamine, and protonation/deprotonation of the Schiff base nitrogen of all-trans-retinal dimer-ethanolamine was pH-dependent. Unconjugated all-trans-retinal dimer was a more efficient generator of singlet oxygen than A2E, and the all-trans-retinal dimer series was more reactive with singlet oxygen than was A2E. By analyzing chromatographic properties and UV-visible spectra together with mass spectrometry, mono- and bis-oxygenated all-trans-retinal dimer photoproducts were detected in Abcr(-/-) mice. The latter findings are significant to an understanding of the adverse effects of retinal pigment epithelial cell lipofuscin.
Department of Ophthalmology, Columbia University, New York, NY 10032, USA.
So R
SR
Kim
Young P
YP
Jang
Steffen
S
Jockusch
Nathan E
NE
Fishkin
Nicholas J
NJ
Turro
Janet R
JR
Sparrow
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D005136:Eye Proteins / Q000235:genetics; D006801:Humans; D008062:Lipofuscin / Q000378:metabolism*; D008268:Macular Degeneration / Q000378:metabolism*; D051379:Mice; D010714:Phosphatidylethanolamines / Q000032:analysis / Q000378:metabolism*; D010857:Pigment Epithelium of Eye / Q000737:chemistry / Q000378:metabolism*; D011726:Pyridinium Compounds / Q000378:metabolism; D012172:Retinaldehyde / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D012176:Retinoids / Q000378:metabolism; D026082:Singlet Oxygen / Q000032:analysis; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D005136:Eye Proteins; D008062:Lipofuscin; D010714:Phosphatidylethanolamines; D011726:Pyridinium Compounds; D012172:Retinaldehyde; D012176:Retinoids; D026082:Singlet Oxygen; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C112040:A2-E (N-retinylidene-N-retinylethanolamine); C512841:Abca4 protein, mouse; C525876:retinal dimer; C525878:retinal dimer ethanolamine; C525877:retinal dimer phosphatidylethanolamine