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Lysosomal dysfunction results in impaired autophagy and increased lipofuscinogenesis 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

We previously demonstrated that photoreceptor outer segments (POS) modified with lipidperoxidation products like 4-hydroxynonenal (HNE) and malondialdehyde (MDA) become stabilised against lysosomal degradation and reduce lysosomal enzyme activities in retinal pigment epithelium (RPE) cells. In this project we analyse whether this lysosomal dysfunction also results in impaired degradation of endogenous cellular proteins (autophagy) and how these two mechanisms contribute to intracellular lipofuscin accumulation which represents a clinical hallmark of age-related macular degeneration (AMD).

 

lipofuscin.jpg

We were able to demonstrate that lysosomal dysfunction induced by phagocytosis of POS modified with lipidperoxidation products inhibits autophagy in RPE cells significantly. Both lysosomal dysfunction and impaired autophagy result in increased cellular lipofuscinogenesis (figure). These mechanisms may be involved in the pathogenesis of RPE changes observed in AMD.

 

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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