Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 47, Pages 23724-23734Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1906643116
Keywords
lysosome; LAMP2; retinal degeneration; aging
Categories
Funding
- Robert Machemer Foundation Vitreoretinal Research Scholarship
- Foundation Lions Eye Research Fund
- Yeatts Family Foundation
- 2013 Macula Society Research Grant award
- Research to Prevent Blindness Physician Scientist Award
- Research to Prevent Blindness Foundation
- National Eye Institute (NEI) [R21EY023079-01/A1, EY014104]
- Loeffler Family fund
- Alcon Research Institute (ARI) Young Investigator Award
- National Institutes of Health (NIH) NEI Core grant [P30EY003790]
- Agence National de la Recherche (ANR), the ERA-Net for Research on Rare Diseases, the Institut Universitaire de France
- Japan Society for the Promotion of Science [19K18880]
- [R01EY025362-01]
- Grants-in-Aid for Scientific Research [19K18880] Funding Source: KAKEN
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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.
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