Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3)

• Published in: Scientific reports Vol. 8; no. 1; pp. 5944 - 14
• Main Authors: Dejos, Camille, Kuny, Sharee, Han, Woo Hyun, Capel, Heather, Lemieux, Hélène, Sauvé, Yves
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.04.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/51; 14/19; 38/77; 38/79; 631/378/2613/1786; 631/80/474/1624; 64/60; 82/58; Cathepsin D; Cell death; Cytotoxicity; Epithelium; Humanities and Social Sciences; Macrophages; Microglia; multidisciplinary; Neurodegenerative diseases; Oxidative stress; Phagocytes; Phagosomes; Photoreceptors; Retina; Retinal pigment epithelium; Rodents; Science; Science (multidisciplinary); Transgenic mice
• DOI: 10.1038/s41598-018-24357-4
• ISSN: 2045-2322

For many neurodegenerative disorders, expression of a pathological protein by one cell type impedes function of other cell types, which in turn contributes to the death of the first cell type. In transgenic mice modelling Stargardt-like (STGD3) maculopathy, human mutant ELOVL4 expression by photoreceptors is associated with defects in the underlying retinal pigment epithelium (RPE). To examine how photoreceptors exert cytotoxic effects on RPE cells, transgenic ELOVL4 (TG1–2 line; TG) and wild-type (WT) littermates were studied one month prior (preclinical stage) to onset of photoreceptor loss (two months). TG photoreceptor outer segments presented to human RPE cells are recognized and internalized into phagosomes, but their digestion is delayed. Live RPE cell imaging pinpoints decreased numbers of acidified phagolysomes. In vivo , master regulator of lysosomal genes, transcription factor EB (TFEB), and key lysosomal enzyme Cathepsin D are both unaffected. Oxidative stress, as ruled out with high-resolution respirometry, does not play a role at such an early stage. Upregulation of CRYBA1/A3 and phagocytic cells (microglia/macrophages) interposed between RPE and photoreceptors support adaptive responses to processing delays. Impaired phagolysosomal maturation is observed in RPE of mice expressing human mutant ELOVL4 in their photoreceptors prior to photoreceptor death and associated vision loss.