[Frontiers in Bioscience E2, 1374-1384, June 1, 2010]

Mechanisms of protein aggregation in the retinal pigment epithelial cells

Kai Kaarniranta1,2, Juha Hyttinen1, Tuomas Ryhanen1, Johanna Viiri1, Tuomas Paimela1, Elisa Toropainen1, Iiris Sorri2, Antero Salminen3,4

1Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland, 2Department of Ophthalmology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland, 3Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211 Kuopio, Finland, 4Department of Neurology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Retinal pigment epithelium (RPE)
4. Lysosomal lipofuscin
5. Proteasomal protein degradation
6. Autophagic clearance
7. The p62/sequestosome 1 as a linker molecule of proteasomes and autophagy
7.1. Multifunctional role of p62
7.2. The p62/sequestosome 1 as a regulator of proteasomal and autophagic clearance
8. Transcytosis in drusen formation
9. Complement system in drusen formation
10. Summary and perspective
11. Acknowledgements
12. References

1. ABSTRACT

The pathogenesis of age-related macular degeneration (AMD) essentially involves chronic oxidative stress, increased accumulation of lipofuscin in retinal pigment epithelial (RPE) cells and extracellular drusen formation, as well as the presence of chronic inflammation. The capacity to prevent the accumulation of cellular cytotoxic protein aggregates is decreased in senescent cells which may evoke lipofuscin accumulation into lysosomes in postmitotic RPE cells. This presence of lipofuscin decreases lysosomal enzyme activity and impairs autophagic clearance of damaged proteins whichshould be removed from cells. Proteasomes are another crucial proteolytic machine which degrade especially cellular proteins damaged by oxidative stress. This review examines the cross-talk between lysosomes, autophagy and proteasomes in RPE cell protein aggregation, their role as a possible therapeutic target and their involvement in the pathogenesis of AMD.