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

First Author  Dejos C Year  2018
Journal  Sci Rep Volume  8
Issue  1 Pages  5944
PubMed ID  29654292 Mgi Jnum  J:262689
Mgi Id  MGI:6163426 Doi  10.1038/s41598-018-24357-4
Citation  Dejos C, et al. (2018) Photoreceptor-induced RPE phagolysosomal maturation defects in Stargardt-like Maculopathy (STGD3). Sci Rep 8(1):5944
abstractText  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.
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