Autophagy and heterophagy dysregulation leads to retinal pigment epithelium dysfunction and development of age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a complex, degenerative and progressive eye disease that usually does not lead to complete blindness, but can result in severe loss of central vision. Risk factors for AMD include age, genetics, diet, smoking, oxidative stress and many cardiovascular-associated risk factors. Autophagy is a cellular housekeeping process that removes damaged organelles and protein aggregates, whereas heterophagy, in the case of the retinal pigment epithelium (RPE), is the phagocytosis of exogenous photoreceptor outer segments. Numerous studies have demonstrated that both autophagy and heterophagy are highly active in the RPE. To date, there is increasing evidence that constant oxidative stress impairs autophagy and heterophagy, as well as increases protein aggregation and causes inflammasome activation leading to the pathological phenotype of AMD. This review ties together these crucial pathological topics and reflects upon autophagy as a potential therapeutic target in AMD.

Keywords: AMD; RPE; autophagy; heterophagy; inflammasome; lysosome; oxidative stress; phagocytosis; proteasome.

Figure 1. Symptoms of AMD include distortion of straight lines, central visual field defects, central dark spots, contrast sensitivity alterations and color-vision impairment.

Figure 2. AMD risk factors associated with different phenotypes of macular degeneration. Phenotypically, AMD can be divided into early and late stages of dry and wet AMD. (A) Pigment mottling and extracellular drusen deposition can be detected in the the early stage of dry AMD (arrow). (B) The late stage of dry AMD develops a large geographic atrophy lesion in the macula (arrow). (C) Hemorrhages are usually observed in the early neovascularization process in wet AMD (arrow). (D) Fibrotic disciform lesion develops in wet AMD if not treated by anti-VEGF agents.

Figure 3. Cross-sectional illustration of the eye and retina. Light reflects via the cornea and lens to the retina. RPE cells have a central role in the pathogenesis of AMD. They absorb light, transport metabolites and nutrients between photoreceptors and the choriocapillaris, produce growth factors, control tissue ionic balance, phagocytose shed tips of photoreceptor outer segments, regulate vitamin A metabolism and visual cycle, and create the blood–retinal barrier. Abbreviations used: R, rods; C, cones; RPE, retinal pigment epithelium; POS, photoreceptor outer segments; BM, Bruch’s membrane; L, lipofuscin; D, drusen; ch, choriocapillaris. Red arrow indicates choroidal neovascularization in the wet AMD process.

Figure 4. Optical coherence images from (A) normal macula structure including physiological foveal pit (arrow) and (B) retinal edema (arrow) in wet AMD. After anti-VEGF intravitreal injection treatment for wet AMD the retinal edema usually regresses to near normal retina thickness. Scale bars: 250 μm.

Figure 5. Transmission electron micrographs of the RPE-Bruch’s membrane/choriocapillaris complex. Typical infoldings of the basal RPE are preserved in wild-type (red arrow, A) and lost in Nuc1 rats (red arrow, B). The cytoplasm of the RPE in Nuc1 rats (red asterisk, B) is more heterogeneous with increased granularity and lipid inclusions as compared with wild type (red asterisk, A). Both thickening and a more heterogeneous composition of Bruch’s membrane (BM) are seen in Nuc1 rats (blue arrowheads, D) as compared with wild type (blue arrowheads, C). A deposit between the basal RPE and BM in Nuc1 rats is indicated in (D) (black arrows). Scale bars: (A and B) 2 μm; (C and D) 500 nm.

Figure 6. Crosstalk between heterophagy and autophagy in the regulation of protein aggregation and inflammation in aged RPE cells. Impaired lysosomal POS clearance increases lipofuscin accumulation that increases oxidative stress damage and protein aggregation in the aged RPE cells. Autophagy flux is decreased due to weakened lysosomal function that also increases mitochondrial damage. All these lead to exocytosis of damaged proteins and activation of the NLRP3 inflammasome in association with drusen formation. Abbreviations used: BM, Bruch’s membrane; UB, ubiquitin.

Figure 7. Pharmacological targets of autophagy. (A) Early stage inhibitors acting upon PIK3CA and MTOR, the most important checkpoints of autophagy induction. (B) Late stage inhibitors of autophagy such as chloroquine and its modified derivatives, and bafilomycin A₁ act upon the autophagy-lysosomal pathway.