Abstract
Chronic degeneration of the Retinal Pigment Epithelium (RPE) is a precursor to pathological changes in the outer retina. The RPE monolayer, which lies beneath the neuroretina, daily internalises and digests large volumes of spent photoreceptor outer segments. Impaired cargo handling and processing in the endocytic/phagosome and autophagy pathways lead to the accumulation of lipofuscin and pyridinium bis-retinoid A2E aggregates and chemically modified compounds such as malondialdehyde and 4-hydroxynonenal within RPE. These contribute to increased proteolytic and oxidative stress, resulting in irreversible damage to post-mitotic RPE cells and development of blinding conditions such as age-related macular degeneration, Stargardt disease and choroideremia. Here, we review how impaired cargo handling in the RPE results in their dysfunction, discuss new findings from our laboratory and consider how newly discovered roles for lysosomes and the autophagy pathway could provide insights into retinopathies. Studies of these dynamic, molecular events have also been spurred on by recent advances in optics and imaging technology. Mechanisms underpinning lysosomal impairment in other degenerative conditions including storage disorders, α-synuclein pathologies and Alzheimer’s disease are also discussed. Collectively, these findings help transcend conventional understanding of these intracellular compartments as simple waste disposal bags to bring about a paradigm shift in the way lysosomes are perceived.
Highlights
The Retinal Pigment Epithelium (RPE) is a monolayer of cells which lies beneath the neuroretina.Amongst its many functions, the RPE internalises photoreceptor outer segments (POS) from overlying photoreceptors as part of the daily visual cycle
The ability to study their dynamic behaviour using novel imaging technologies, discoveries revealing new roles for lysosomes and autophagosomes, and the ability to study their we review the topic of how RPE cells cope with the high proteolytic burden in the senescent retina, dynamic behaviour using novel imaging technologies, we review the topic of how RPE cells cope and why its impairment leads to irreversible blindness
A noteworthy component recruited to the cytosolic surface of EEs as well as maturing late endosomes (LEs) is the ‘retromer’; a multimeric complex composed of sorting nexins and associated proteins that mediates the retrograde retrieval of cargos from endosomes to the plasma membrane or to the trans-Golgi network for re-use [21]
Summary
The Retinal Pigment Epithelium (RPE) is a monolayer of cells which lies beneath the neuroretina. The substantial metabolic waste generated in the outer retina is removed via the underlying choriocapillaris [6,7] Sandwiched between this dense capillary network and the RPE is a porous tissue of 2–4 μm thickness referred to as Bruch’s membrane (BrM) which supports the overlying cell monolayer (Figure 1). This, coupled with the fact that in-situ, RPE are largely post-mitotic, makes the each cell is exposed to 2000 discs per day in the parafovea, 3500 in the perifovea and approximately proteolytic burden in these cells considerable. Studies in Rhesus monkeys showed that each cell is 4000 in the periphery, with each RPE processing up to a billion photoreceptor disks over a 70-year exposed to 2000 discs per day in the parafovea, 3500 in the perifovea and approximately 4000 in the period [2].
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