Molecular mechanisms of phagosome maturation and degradation in the retinal pigment epithelium in health and disease

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The retinal pigment epithelium (RPE) is a single cell layer in the eye that lies immediately beneath the photoreceptors, the cells that detect light. Photoreceptors must undergo a process of daily partial renewal in order to function properly. Everyday at about the onset of daylight, photoreceptors shed their tips, which are engulfed (phagocytosed) by the RPE and degraded. RPE cells do not normally divide in the adult so a single RPE cell phagocytoses and degrades an enormous amount of photoreceptor material during a 70 year lifespan. This prodigious activity takes its toll and as the RPE ages undigested products of phagocytosis accumulate within the cells and this is believed to contribute to the accumulation of debris with age, particularly in people suffering from age-related macular degeneration, the leading cause of blindness in the Western world. Whilst considerable progress has recently been made in identifying the molecules that regulate the initial engulfment process, much less is known about what regulates the subsequent degradation of the vacuole containing the phagocytosed material (the phagosome). In cells where phagosome degradation has been better characterised the phagosome has been shown to undergo a maturation process involving the sequential acquisition of specific proteins that are necessary for the phagosome to gain the ability to fuse with the lysosome. Within the lysosome enzymes degrade the phagosome. Using high resolution microscopic methods we will identify the transport steps required for phagocytosed photoreceptor outer segments to be delivered to the lysosome and degraded. We will then determine which molecules regulate phagosome maturation and degradation in RPE cells, focussing on Rab proteins and motor proteins, some of which we have already shown are present in RPE cells and regulate other transport steps within the cell. This study will identify mechanisms whereby a process that is essential to human vision takes place and will help us to understand how this process breaks down with age and in eye disease.