Novel lipofuscin bisretinoids prominent in human retina and in a model of recessive Stargardt disease.

Abstract

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.

• Authors: Yalin Wu, Nathan E Fishkin, Ajay Pande, Jayanti Pande, Janet R Sparrow
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 30 Pg. 20155-66 (Jul 24 2009) ISSN: 0021-9258 [Print] United States
• PMID: 19478335 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• Diterpenes
• Lipofuscin
• vitamin A-aldehyde-dihydropyridine-ethanolamine
• vitamin A-aldehyde-dihydropyridine-phosphatidylethanolamine
• Vitamin A
• Retinaldehyde

Topics

• ATP-Binding Cassette Transporters (genetics)
• Age Factors
• Animals
• Cattle
• Chromatography, High Pressure Liquid
• Diterpenes
• Humans
• Lipofuscin (analogs & derivatives, analysis, isolation & purification, metabolism)
• Macular Degeneration (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Molecular
• Molecular Structure
• Pigment Epithelium of Eye (chemistry)
• Retina (chemistry)
• Retinaldehyde (metabolism)
• Spectroscopy, Fourier Transform Infrared
• Tandem Mass Spectrometry
• Vitamin A (analogs & derivatives, analysis, isolation & purification, metabolism)