Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 47; pp. 23724 - 23734
• Main Authors: Notomi, Shoji, Ishihara, Kenji, Efstathiou, Nikolaos E., Lee, Jong-Jer, Hisatomi, Toshio, Tachibana, Takashi, Konstantinou, Eleni K., Ueta, Takashi, Murakami, Yusuke, Maidana, Daniel E., Ikeda, Yasuhiro, Kume, Shinji, Terasaki, Hiroto, Sonoda, Shozo, Blanz, Judith, Young, Lucy, Sakamoto, Taiji, Sonoda, Koh-Hei, Saftig, Paul, Ishibashi, Tatsuro, Miller, Joan W., Kroemer, Guido
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.11.2019
• Series: PNAS Plus
• Subjects: Abnormalities; Accumulation; Age; Age related diseases; Aging - genetics; Aging - pathology; Animals; Apolipoprotein E; Basal lamina; Basement Membrane - pathology; Bioaccumulation; Biological Sciences; Bruch Membrane - pathology; Clonal deletion; Clusterin; Collagen; Degradation; Epithelium; Exocytosis; Extracellular matrix; Eye diseases; Fibronectin; Gene deletion; Gene expression; Glycoproteins; Humans; Laminin; Life Sciences; Lysosomal-Associated Membrane Protein 2 - genetics; Lysosomal-Associated Membrane Protein 2 - metabolism; Lysosomes; Lysosomes - metabolism; Macular degeneration; Macular Degeneration - genetics; Macular Degeneration - metabolism; Medicin och hälsovetenskap; Membrane proteins; Membranes; Mice; Mice, Knockout; Phagocytes; Phagocytosis; Phagosomes; Photoreceptors; PNAS Plus; Proteins; Retina; Retina - pathology; Retinal pigment epithelium; Retinal Pigment Epithelium - metabolism; Thickening; Vitronectin; retinal degeneration; aging; lysosome; LAMP2
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1906643116

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.