Yasuhiro Ikeda, Lucy H. Young, Koh Hei Sonoda, Paul Saftig, Tatsuro Ishibashi, Demetrios G. Vavvas, Daniel E. Maidana, Yusuke Murakami, Eleni K. Konstantinou, Nikolaos Efstathiou, Shinji Kume, Taiji Sakamoto, Toshio Hisatomi, Hiroto Terasaki, Shozo Sonoda, Takashi Tachibana, Takashi Ueta, Shoji Notomi, Joan W. Miller, Guido Kroemer, Jong Jer Lee, Kenji Ishihara, and Judith Blanz
Significance Extracellular tissue debris accumulates with aging and in the most prevalent central-vision-threatening eye disorder, age-related macular degeneration (AMD). In this work, we discovered that lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes, is preferentially expressed in the outermost, neuroepithelial layer of the retina, the retinal pigment epithelium (RPE), and contributes to the prevention of ultrastructural changes in extracellular basolaminar deposits including lipids and apolipoproteins. LAMP2 thus appears to play an important role in RPE biology, and its apparent decrease with aging and in AMD specimens suggests that its deficiency may accelerate the basolaminar deposit formation and RPE dysfunction seen in these conditions., The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium (RPE) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by RPE cells, and its expression declined with age. Deletion of the Lamp2 gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch’s membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD—namely, the accumulation of APOE, APOA1, clusterin, and vitronectin—adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting RPE basal lamina and Bruch’s membrane were reduced in Lamp2 knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient RPE cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the RPE and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in RPE function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.