Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration

Increased accumulation of lipofuscin in cells of the retinal pigment epithe lium (RPE) is seen in several forms of macular degeneration, a common cause of blindness in humans. A major fluorophore of lipofuscin is the toxic bis -retinoid, N-retinylidene-N-retinylethanolamine (A2E). Previously, we gener ated mice with a knockout mutation in the abcr gene. This gene encodes rim protein (RmP), an ATP-binding cassette transporter in rod outer segments, M ice lacking RmP accumulate A2E in RPE cells at a greatly increased rate ove r controls. Here, we identify three precursors of A2E in ocular tissues fro m abcr-1- mice and humans with ABCR-mediated recessive macular degeneration s. Our results corroborate the scheme proposed by C. A. Parish, M. Hashimot o, K. Nakanishi, J. Dillon & J. Sparrow [Proc. Natl. Acad. Sci. USA (1998) 95, 14609-14613], for the biosynthesis of A2E: (i) condensation of all-tran s-retinaldehyde (all-trans-RAL) with phosphatidylethanolamine to form a Sch iff base; (ii) condensation of the amine product with a second all-trans-RA L to form a bis-retinoid; (iii) oxidation to yield a pyridinium salt; and ( iv) hydrolysis of the phosphate ester to yield A2E. The latter two reaction s probably occur within RPE phagolysosomes. As predicted by this model, for mation of A2E was completely inhibited when abcr-/- mice were raised in tot al darkness. Also, once formed, A2E was not eliminated by the RPE. These da ta suggest that humans with retinal or macular degeneration caused by loss of RmP function may slow progression of their disease by limiting exposure to light. The precursors of A2E identified in this study may represent phar macological targets for the treatment of ABCR-mediated macular degeneration .