Purchase this article with an account.
Jingyu Yao, Lin Jia, Naheed W Khan, Cheng-mao Lin, Joshua L Dunaief, Michael E Boulton, Daniel Klionsky, Jun-Lin Guan, Debra A Thompson, David N Zacks; Autophagy in the retinal pigment epithelium: Insights into age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4560.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Autophagy is an important intracellular pathway critical for maintaining cellular homeostasis and regulating the response to environmental stressors. The purpose of this study is to determine the effect of selectively knocking out FIP200 (FAK family-interacting protein of 200 kDa), an upstream activator of autophagy, from the retinal pigment epithelium (RPE).
Fip200 was selectively deleted from the RPE by crossing BEST1-Cre mice, in which Cre-combinase expresses specifically in the RPE, with mice containing the Fip200 gene flanked with Lox-P sites (Fip200flox/flox). We performed ex vivo and in vivo analyses to assess retinal structure and function.
Deletion of Fip200 from the RPE results in defective autophagy activation in these cells, as evidenced by decreased conversion of LC3-I to LC3-II and accumulation of p62/SQSTM1. Suppression of autophagy in the mouse RPE leads to age-dependent degeneration of the RPE with formation of atrophic patches, microglial cell activation in the affected areas, sub-RPE deposition of inflammatory and oxidatively damaged proteins, subretinal drusenoid deposits, and occasional foci of choroidal neovascularization that appears similar to those are found in age-related macular degeneration (AMD). There is also a secondary loss of the photoreceptor cells overlying the degenerated RPE and resultant reduction in the electroretinogram.
Suppression of autophagy activation specifically in the RPE by deletion of Fip200 causes age-dependent degeneration of the RPE and, secondarily, photoreceptor death, resulting in a retinal phenotype that appears similar to that seen in patients with AMD. Together, these observations provide evidence suggesting a critical function of autophagy in the maintenance of normal cellular homeostasis in the aging RPE.
This PDF is available to Subscribers Only