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Oxidatively damaged POS induce lysosomal dysfunction in RPE cells

Dr. med. Tim U. Krohne
Nina K. Stratmann, MD student
Claudine Strack, BTA
Prof. Dr. med. Frank G. Holz

 

In cooperation with:
Dr. med. E. Kämmerer
Dr. sc. hum. Marion Bergmann
Sigrun Himmelsbach, MTA
Prof. Dr. rer. nat. J. Kopitz
(Department of Molecular Pathology, University of Heidelberg)

 

Summary

A hallmark of early-stage age-related macular degeneration (AMD) is the progressive accumulation of abnormal material at the level of the retinal pigment epithelium (RPE), finally forming lipofuscin granules and drusen. These intra- and extracellular deposits are thought to result from incompletely digested material secondary to impaired lysosomal capacity.

In the macula, constant light exposure, along with high oxygen levels, triggers permanent peroxidation of lipids in the photoreceptor outer segment (POS) membranes. Products of lipid peroxidation like 4-hydroxynonenal (HNE) and malondialdehyde (MDA) are able to bind covalently to proteins, resulting in impaired protein function. In this project we study the effect of HNE and MDA on RPE lysosomal enzyme activities.

 lysosomaldysfunction.jpg

We were able to demonstrate that lipid peroxidation products like HNE and MDA induce lysosomal dysfunction in human RPE cells via three different mechanisms (figure).

 

References

Krohne TU, Holz FG, Kopitz J.
Apical-to-basolateral transcytosis of photoreceptor outer segments induced by lipid peroxidation products in human retinal pigment epithelial cells.
Invest Ophthalmol Vis Sci 2010 Jan;51(1):553-60. [PubMed abstract]

Krohne TU, Kaemmerer E, Holz FG, Kopitz J.
Lipid peroxidation products reduce lysosomal protease activities in human retinal pigment epithelial cells via two different mechanisms of action.
Exp Eye Res 2010 Feb;90(2):261-6. [PubMed abstract]

Krohne TU, Stratmann NK, Kopitz J, Holz FG.
Effects of lipid peroxidation products on lipofuscinogenesis and autophagy in human retinal pigment epithelial cells.
Exp Eye Res 2010 Mar;90(3):465-71. [PubMed abstract]

Kaemmerer E, Schutt F, Krohne TU, Holz FG, Kopitz J.
Effects of lipid peroxidation-related protein modifications on RPE lysosomal functions and POS phagocytosis.
Invest Ophthalmol Vis Sci. 2007 Mar;48(3):1342-7. [PubMed abstract]

Krohne TU, Bergmann M, Holz FG, Kopitz J.
VEGF isoforms are differentially induced by lipidperoxidation products in human retinal pigment epithelial cells.
German Ophtholmological Society (DOG), Annual Meeting 2006, Berlin. [DOG abstract]

Holz FG, Kämmerer E, Bindewald A, Kopitz J.
Effects of Lipidperoxidation-related Protein Modifications on RPE Lysosomal Functions, ROS Phagocytosis and their Impact for Lipofuscinogenesis.
Invest Ophthalmol Vis Sci 2004;45:E-Abstract 3385. [ARVO abstract]

Bergmann M, Schutt F, Holz FG, Kopitz J.
Inhibition of the ATP-driven proton pump in RPE lysosomes by the major lipofuscin fluorophore A2-E may contribute to the pathogenesis of age-related macular degeneration.
FASEB J. 2004 Mar;18(3):562-4. [PubMed abstract]

Schutt F, Bergmann M, Holz FG, Kopitz J.
Proteins modified by malondialdehyde, 4-hydroxynonenal, or advanced glycation end products in lipofuscin of human retinal pigment epithelium.
Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3663-8. [PubMed abstract]

Schutt F, Ueberle B, Schnolzer M, Holz FG, Kopitz J.
Proteome analysis of lipofuscin in human retinal pigment epithelial cells.
FEBS Lett. 2002 Sep 25;528(1-3):217-21. [PubMed abstract]

 

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