The endolysosomal system and AMD: Insights from a novel genetically engineered mouse model

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Abstract

In phagocytic cells, the endolysosomal system is a crucial regulator of both phagocytosis and autophagy, thereby helping to maintain cellular homeostasis. Prime examples of this are retinal pigmented epithelial (RPE) cells, which are not only among the most actively phagocytic cells, continuously phagocytosing shed photoreceptor outer segments (OS), but also are post-mitotic cells having high metabolic activity and a high rate of autophagy. For proper RPE function, and to ensure the functional integrity of the neural retina, both phagocytosis and autophagy need to be in balance. We show that in the RPE, bA3/A1-crystallin is required for normal lysosomal-mediated waste removal. Our studies suggest that bA3/A1-crystallin acts via the AMPK-mTORC1 signaling pathway. Based on our findings, we postulate that loss of bA3/A1-crystallin inhibits these signaling pathways, leading to a defect in the V-ATPase-mediated acidification of the lysosomal machinery. Since bA3/A1-crystallin has been reported to be present in human drusen and a possible role for lysosomes in age-related macular degeneration (AMD) has been suggested, it is possible that perturbation of normal phagocytosis/autophagy in RPE could cause some manifestations of AMD.

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