Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease.
Bisretinoid adducts accumulate as lipofuscin in retinal pigment epithelial (RPE) cells of the eye and are implicated in the pathology of inherited and age-related macular degeneration. Characterization of the bisretinoids A2E and the all-trans-retinal dimer series has shown that these pigments form from reactions in photoreceptor cell outer segments that involve all-trans-retinal, the product of photoisomerization of the visual chromophore 11-cis-retinal. Here we have identified two related but previously unknown RPE lipofuscin compounds. By high performance liquid chromatography-electrospray ionization-tandem mass spectrometry, we determined that the first of these compounds is a phosphatidyl-dihydropyridine bisretinoid; to indicate this structure and its formation from two vitamin A-aldehyde (A2), we will refer to it as A2-dihydropyridine-phosphatidylethanolamine (A2-DHP-PE). The second pigment, A2-dihydropyridine-ethanolamine, forms from phosphate hydrolysis of A2-DHP-PE. The structure of A2-DHP-PE was corroborated by Fourier transform infrared spectroscopy, and density functional theory confirmed the presence of a dihydropyridine ring. This lipofuscin pigment is a fluorescent compound with absorbance maxima at approximately 490 and 330 nm, and it was identified in human, mouse, and bovine eyes. We found that A2-DHP-PE forms in reaction mixtures of all-trans-retinal and phosphatidylethanolamine, and in mouse eyecups we observed an age-related accumulation. As compared with wild-type mice, A2-DHP-PE is more abundant in mice with a null mutation in Abca4 (ATP-binding cassette transporter 4), the gene causative for recessive Stargardt macular degeneration. Efforts to clarify the composition of RPE lipofuscin are important because these compounds are targets of gene-based and drug therapies that aim to alleviate ABCA4-related retinal disease.
Wu
Yalin
Y
Department of Ophthalmology, Columbia University, New York, New York 10032, USA.
Fishkin
Nathan E
NE
Pande
Ajay
A
Pande
Jayanti
J
Sparrow
Janet R
JR
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000367:Age Factors; D000818:Animals; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D004224:Diterpenes; D006801:Humans; D008062:Lipofuscin / Q000031:analogs & derivatives / Q000032:analysis* / Q000302:isolation & purification / Q000378:metabolism*; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D010857:Pigment Epithelium of Eye / Q000737:chemistry*; D012160:Retina / Q000737:chemistry*; D012172:Retinaldehyde / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared; D053719:Tandem Mass Spectrometry; D014801:Vitamin A / Q000031:analogs & derivatives / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D004224:Diterpenes; D008062:Lipofuscin; C543677:vitamin A-aldehyde-dihydropyridine-ethanolamine; C543676:vitamin A-aldehyde-dihydropyridine-phosphatidylethanolamine; D014801:Vitamin A; D012172:Retinaldehyde