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Prog Retin Eye Res. 2018 Dec 17. pii: S1350-9462(18)30041-7. doi: 10.1016/j.preteyeres.2018.12.003. [Epub ahead of print]

On the origin of proteins in human drusen: The meet, greet and stick hypothesis.

Author information

1
Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands; Department of Ophthalmology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands; Netherlands Institute for Neuroscience (NIN-KNAW), Amsterdam, the Netherlands. Electronic address: aabergen@amc.uva.nl.
2
School of Medicine, University of St Andrews, St Andrews, United Kingdom.
3
Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
4
UCL Institute of Ophthalmology, University College London, London, UK.
5
School of Medicine, University of St Andrews, St Andrews, United Kingdom; Division of Biomaterials and Tissue Engineering, UCL Eastman Dental Institute, UCL, London, UK.
6
Deptartment of Pathology, Division Clinical Bioinformatics, Erasmus MC, Rotterdam, the Netherlands.
7
Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
8
Department of Ophthalmology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands; Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
9
Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, Northern Ireland, UK.
10
UCL Institute of Ophthalmology, University College London, London, UK; Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, Northern Ireland, UK.

Abstract

Retinal drusen formation is not only a clinical hallmark for the development of age-related macular degeneration (AMD) but also for other disorders, such as Alzheimer's disease and renal diseases. The initiation and growth of drusen is poorly understood. Attention has focused on lipids and minerals, but relatively little is known about the origin of drusen-associated proteins and how they are retained in the space between the basal lamina of the retinal pigment epithelium and the inner collagenous layer space (sub-RPE-BL space). While some authors suggested that drusen proteins are mainly derived from cellular debris from processed photoreceptor outer segments and the RPE, others suggest a choroidal cell or blood origin. Here, we reviewed and supplemented the existing literature on the molecular composition of the retina/choroid complex, to gain a more complete understanding of the sources of proteins in drusen. These "drusenomics" studies showed that a considerable proportion of currently identified drusen proteins is uniquely originating from the blood. A smaller, but still large fraction of drusen proteins comes from both blood and/or RPE. Only a small proportion of drusen proteins is uniquely derived from the photoreceptors or choroid. We next evaluated how drusen components may "meet, greet and stick" to each other and/or to structures like hydroxyapatite spherules to form macroscopic deposits in the sub-RPE-BL space. Finally, we discuss implications of our findings with respect to the previously proposed homology between drusenogenesis in AMD and plaque formation in atherosclerosis.

KEYWORDS:

Age-related macular degeneration (AMD); Alzheimer's disease; Blood; Bruch's membrane; Drusen proteins; Retinal pigment epithelium (RPE)

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