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(Investigative Ophthalmology and Visual Science. 2003;44:3663-3668.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-0172
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Proteins Modified by Malondialdehyde, 4-Hydroxynonenal, or Advanced Glycation End Products in Lipofuscin of Human Retinal Pigment Epithelium

Florian Schutt,1,2 Marion Bergmann,2 Frank G. Holz,1 and Jurgen Kopitz2

1From the Departments of Ophthalmology, and 2Molecular Pathology, University of Heidelberg, Heidelberg, Germany.

PURPOSE. Lipofuscin (LF) accumulation in the retinal pigment epithelium (RPE) is associated with age and various retinal diseases. Toxic LF compounds may interfere with normal RPE function. Oxidative modification of proteins was determined in LF granules from human eyes.

METHODS. LF was isolated from the RPE-choroid complex of 10 pairs of donor eyes by gradient ultracentrifugation. Protein compounds were separated by two-dimensional (2-D) gel electrophoresis and screened by Western blot analysis for lipid peroxidation- or glucoxidation-induced damage—in particular, by malondialdehyde (MDA), 4-hydroxynonenal (HNE), and advanced glycation end products (AGEs). Identity of the immunostained proteins was revealed using 2-D software for comparison of the spot position with Coomassie-stained 2-D gels of the same samples.

RESULTS. By comparing the results taken from the authors’ previous proteome analysis of RPE LF with an immunoblot analysis of the same samples, this study shows that a variety of LF-associated proteins were damaged by aberrant covalent modifications of MDA, 4-HNE, and AGEs. Several proteins were altered by two or three different modification types. Modified mitochondrial proteins indicated that autophagy of altered proteins also contributed to lipofuscin formation.

CONCLUSIONS. The identification of lipid peroxidation and glucoxidation products in proteinaceous LF components in human RPE supports the hypothesis that these compounds are involved in lipofuscinogenesis and may contribute to the cytotoxic effects of LF in retinal diseases such as age-related macular degeneration and Stargardt disease. Their identification may help to identify potential future treatment targets.




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