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Guillermo Lehmann-Mantaras, Nazia M Alam, Ignacio Benedicto, Kristopher Barnes, Mohammed Ahmadi, Glen Prusky, Enrique Rodriguez-Boulan, Marcelo Nociari; ER-stress parallels RPE degeneration in animal model of lipofuscin-driven retinal disease. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4219.
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Lipofuscin (LF) is a hallmark of aging. It is usually called “the age pigment” because its amount increases with age, but more importantly, because its accumulation rate inversely correlates with longevity. In the past few years it has become evident that LF accumulation leads to cell dysfunction and death; however, interventions to reverse accumulation have not been developed.
The retinal pigment epithelium (RPE) is one of the tissues most affected by age-related LF buildup. LF accumulation in RPE lysosomes is a demonstrated cause of Stargardt disease. Furthermore, LF accumulation can be reproduced in vitro in RPE cell cultures, providing a model system for studying the pathophysiology of LF. In the present work we analyzed the consequences of LF accumulation in RPE a) in vitro by using cultured RPE cells loaded with LF, and b) in vivo by using the ABCA4-/-RDH8-/- double knockout (DKO) mice as a model of LF-induced retinal degeneration.
We demonstrate that in vitro, LF induces a dose dependent RPE cell death through unresolved ER-stress. The ABCA4-/-RDH8-/- DKO mice exhibit increasing levels of ER stress which are age-related. Behavioral measures of visual function with opto-kinetic tracking in the mice reveals that they have normal function until 18-20 months, which then declines rapidly. The vision loss is associated with increased levels of the ER stress marker Xbp1s in RPE, but not in the neural retina.
Since the lost of vision corresponds with a selective degeneration and death of RPE cells, these experiments are consistent with a model in which age-related ER stress, resulting from the accumulation of LF, leads to retinal degeneration and blindness.
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