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

Shoji Notomi, Kenji Ishihara, Nikolaos E. Efstathiou, Jong Jer Lee, Toshio Hisatomi, Takashi Tachibana, Eleni K. Konstantinou, Takashi Ueta, Yusuke Murakami, Daniel E. Maidana, Yasuhiro Ikeda, Shinji Kume, Hiroto Terasaki, Shozo Sonoda, Judith Blanz, Lucy Young, Taiji Sakamoto, Koh Hei Sonoda, Paul Saftig, Tatsuro IshibashiJoan W. Miller, Guido Kroemer, Demetrios G. Vavvas

研究成果: Contribution to journalArticle査読

16 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)23724-23734
ページ数11
ジャーナルProceedings of the National Academy of Sciences of the United States of America
116
47
DOI
出版ステータス出版済み - 2019

All Science Journal Classification (ASJC) codes

  • 一般

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