Light exposure stimulates formation of A2E oxiranes in a mouse model of Stargardt's macular degeneration.
Recessive Stargardt's macular degeneration is a blinding disease of children caused by mutations in the ABCA4 (ABCR) gene. Mice with a knockout mutation in abcr accumulate toxic lipofuscin pigments in ocular tissues, similar to affected humans. The major fluorophore of lipofuscin is the bis-retinoid, N-retinylidene-N-retinylethanolamine (A2E). In the current study, we sought to define the effect of increasing light on A2E accumulation. We crossed the abcr(-/-) mutation onto an albino background. The retinoid profiles in albino mice indicated higher retinal illuminance than in pigmented mice exposed to similar ambient light. Unexpectedly, A2E levels were not higher in the albino mice. Also, A2E levels in abcr(-/-) mice reared under cyclic light at 30, 120, or 1,700 lux were similar. Thus, increased retinal illuminance was not correlated with higher A2E. A2E has been shown to undergo light-dependent oxidation to yield a series of A2E epoxides or oxiranes. These oxiranes react with DNA in vitro, suggesting a potential mechanism for A2E cytotoxicity. We analyzed ocular tissues from abcr(-/-) mice for A2E oxiranes by mass spectrometry. Unlike A2E, the oxiranes were more abundant in albino vs. pigmented abcr(-/-) mice, and in abcr(-/-) mice exposed to increasing ambient light. These observations suggest that both the biosynthesis of A2E and its conversion to oxiranes are accelerated by light. Finally, we showed that the formation of A2E oxiranes is strongly suppressed by treating the abcr(-/-) mice with Accutane (isotretinoin), an inhibitor of rhodopsin regeneration.
Radu
Roxana A
RA
Jules Stein Eye Institute and Department of Biological Chemistry, School of Medicine, University of California, Los Angeles, CA 90095, USA.
Mata
Nathan L
NL
Bagla
Aarti
A
Travis
Gabriel H
GH
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000222:Adaptation, Physiological; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005027:Ethylene Oxide / Q000032:analysis / Q000378:metabolism*; D015474:Isotretinoin / Q000494:pharmacology; D008027:Light; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C
D018528:ATP-Binding Cassette Transporters; C512841:Abca4 protein, mouse; D015474:Isotretinoin; D005027:Ethylene Oxide