Macular Degeneration: Kaemmerer E

Kopitz J, Holz FG, Kaemmerer E, Schutt F. · Institute of Molecular Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany. <> · Biochimie. · Pubmed #15589692 No free full text.

Abstract: In people over 50, age-related macular degeneration (ARMD) has become the most common cause for severe visual loss and legal blindness in all industrialized nations. Currently, there is no effective treatment for the majority of patients. To develop new and effective modes of therapy, understanding of the molecular basis of the disease in mandatory. However, the pathogenesis of ARMD is still poorly understood. Several lines of evidence suggest that aging changes of the retinal pigment epithelium (RPE), in particular the accumulation of autofluorescent lipofuscin granules in the lysosomal compartment of postmitotic RPE cells, play a key role in the pathogenesis of the disease. Recent studies indicate that lipidic compounds of lipofuscin, represented by the retinoid A2-E, and protein damage by lipid peroxidation products, in particular malondialdehyde and 4-hydroxynonenal, induce lysosomal dysfunction and lipofuscinogenesis in the RPE. The possible mechanisms underlying this lysosomal dysfunction and the resulting adverse effects on overall RPE function are discussed.

Kaemmerer E, Schutt F, Krohne TU, Holz FG, Kopitz J. · Department of Pathology, University of Heidelberg, Heidelberg, Germany. · Invest Ophthalmol Vis Sci. · Pubmed #17325182 links to  free full text

Abstract: PURPOSE: Lipofuscin accumulation in the RPE is a common downstream pathogenic pathway in various monogenic and complex retinal diseases including age-related macular degeneration (AMD). Lipid peroxidation-induced modification of proteins is thought to play a role in lipofuscinogenesis and may contribute to RPE dysfunction. A prior study demonstrated that a variety of lipofuscin-associated proteins are damaged by aberrant covalent modifications of malondialdehyde (MDA) and 4-hydroxynonenal (HNE). The present study was conducted to test the hypothesis that these damaged proteins are more resistant to proteolytic attack and act as protease inhibitors. METHODS: Isolated photoreceptor outer segments (POS) were radioactively labeled and in vitro modified with MDA and HNE. Pure lysosomal fractions isolated from human RPE were tested for their proteolytic activities toward modified and unmodified POS proteins. In parallel, modified and radiolabeled POS were fed to RPE cell cultures for phagocytosis and their lysosomal degradation as well as intracellular accumulation was compared with unmodified POS. RESULTS: Both experimental approaches revealed that MDA or HNE modifications strikingly increase the resistance of POS proteins to the attack by lysosomal proteases. When cultured RPE cells were fed with modified or unmodified POS the amount of degraded POS proteins was reduced by approximately 60% to 70% for the modified POS compared with those in normal control subjects. Some of the modified proteins remained undegraded in the lysosomal compartment of cultured RPE cells and were still detectable 3 weeks after feeding, whereas unmodified POS were completely degraded within 1 week after feeding. Moreover, modified proteins had the potential to impair degradation of unmodified proteins, indicating their efficacy as proteolytic antagonists. CONCLUSIONS: The results indicate that lipid peroxidation-derived protein modifications are involved in lipofuscinogenesis and may contribute to cell damaging effects of lipofuscin in retinal diseases such as AMD.