The lipofuscin component A2E selectively inhibits phagolysosomal degradation of photoreceptor phospholipid by the retinal pigment epithelium.
Daily phagocytosis of spent photoreceptor outer segments is a critical maintenance function performed by the retinal pigment epithelium (RPE) to preserve vision. Aging RPE accumulates lipofuscin, which includes N-retinylidene-N-retinylethanolamine (A2E) as the major autofluorescent component. We studied the effect of physiological levels of A2E in RPE cultures on their ability to phagocytose outer segments. A2E localized to lysosomes in cultured RPE as well as in human RPE in situ. A2E-loaded RPE cells in culture bound and internalized identical numbers of outer segments as control RPE indicating that A2E does not alter early steps of phagocytosis. A2E-loaded RPE degraded outer segment proteins efficiently but, strikingly, failed to completely digest phospholipids within 24 h. Because of the circadian rhythm of RPE phagocytosis in the eye, a delay in lipid degradation would likely result in a build up of undigested material in RPE that could contribute to the development of age-related macular degeneration.
Finnemann
Silvia C
SC
Margaret M. Dyson Vision Research Institute, Department of Ophthalmology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Leung
Lawrence W
LW
Rodriguez-Boulan
Enrique
E
D002460:Cell Line; D016650:Fluorescein-5-isothiocyanate; D005455:Fluorescent Antibody Technique; D006801:Humans; D008062:Lipofuscin / Q000737:chemistry* / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008268:Macular Degeneration / Q000378:metabolism; D008875:Middle Aged; D010587:Phagocytosis / Q000187:drug effects*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D010786:Photoreceptor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011726:Pyridinium Compounds / Q000494:pharmacology*; D012176:Retinoids / Q000494:pharmacology*
C112040:A2-E (N-retinylidene-N-retinylethanolamine); D008062:Lipofuscin; D008081:Liposomes; D010713:Phosphatidylcholines; D010743:Phospholipids; D011726:Pyridinium Compounds; D012176:Retinoids; C044745:1-palmitoyl-2-(6-(N-(7-nitrobenz)-2-oxa-1,3-diazol-4-yl)aminocaproyl)phosphatidylcholine; D016650:Fluorescein-5-isothiocyanate