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Lysosomes are dynamic organelles involved in cellular clearance processes.It has been suggested that chronic impairment of cellular clearance may be a major driving force behind a variety of age-related diseases.While abnormalities in lysosome function of retinal pigment epithelial (RPE) cells are considered to be significant risk factors for age-related macular degeneration (AMD), it is not clear how such abnormalities affect the disease process.We recently provided novel evidence that bA3/A1-crystallin (herein referred to as bA3/A1), acting through V-ATPase (vacuolar-type H+-ATPase)/mTORC1 (mechanistic target of rapamycin complex 1) signaling, is essential for normal autophagy-mediated clearance in the RPE cells.βbA3/A1, a member of the b/g-crystallin superfamily is expressed in the lens, astrocytes and RPE cells.Interestingly, V-ATPase-mTORC1 signaling has been implicated as an essential mechanism for maintenance of lysosomal homeostasis in other systems.Our mouse model,the Cryba1 (gene encoding bA3/A1) cKO (conditional knockout) mice are characterized by RPE atrophy, scattered vacuoles, accumulation of autophagosomes, basal laminar deposits, retinal degeneration and immune cell infiltration.Impaired lysosomal clearance in the RPE of aging Cryba1 cKO mice results in the loss of RPE65, an isomerohydrolase that is involved in the conversion of all-trans retinyl ester to 11-cis retinol in the visual cycle.We also observed a significant increase in cleaved caspase-3 positive cells as well as phosphorylation of BAD protein at Ser 136 and 155 in the Cryba1 cKO RPE, indicating increased cell death.AMD is one of the leading causes of blindness in developed countries and elucidating the mechanism(s)of RPE cell death in AMD will uncover new avenues for therapy and prevention.We have developed a unique model system in which to study the autophagy mechanisms in RPE cells and how abnormalities in this process can lead to diseases affecting RPE, such as AMD.