Photosensitization of A2E triggers telomere dysfunction and accelerates retinal pigment epithelium senescence

Abstract

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in elderly people. AMD is classified as early, intermediate, advanced non-neovascular, and advanced neovascular forms depending on the clinical features. However, the exact pathogenesis remains unclear. Retinal pigment epithelium (RPE) cells degeneration is a hallmark of AMD. With aging, lipofuscin accumulates in RPE cells. N-retinylidene-N-retinylethanolamine (named A2E), a well-known fluorophore of lipofuscin, may contribute to RPE cells degeneration. In this study, we showed that photosensitization of A2E increased DNA damage, including telomere deprotection and deletion, and triggered cellular senescence. In addition, we found that the antioxidant N-acetyl-cysteine (NAC) partially alleviated this DNA damage. Telomerase overexpression rescued A2E-mediated RPE cell senescence, indicating that telomere dysfunction plays an important role in A2E-based senescence. We further showed that the senescence induced by A2E photosensitization may affect the microenvironment of the retina by expressing several factors of the secretory phenotype (SASP) including IL1B, IL13RA2, and CXCR4 through the NF-κB pathway. We propose that expression of these factors create a pro-inflammatory environment that drives retina degeneration. Moreover, our findings suggest that protecting telomeres is a valuable strategy for treating retinal degeneration diseases, such as AMD.

Effects of A2E-Induced Oxidative Stress on Retinal Epithelial Cells: New Insights on Differential Gene Response and Retinal Dystrophies

“…Photosensitization of A2E stimulates oxidative DNA damage, such as the production of 8-oxo-guanines in telomeres, leading to their possible damage [57]. Thus, the resulted alteration of telomerase RNA localization to Cajal body could accelerate the RPE senescence [58], and this process could be further increased by the reduction of FGFR1 signaling and the consequent POS phagocytosis decrease [59]. Moreover, DNA damage response could increase the activity of miRNAs involved in [60,61] and cell death genes transcription by TP53 [62], determining a possible role in retina degeneration.…”

Perfluorooctanoic acid in indoor particulate matter triggers oxidative stress and inflammation in corneal and retinal cells

“…The flasks were tightly sealed, and air was passed through the flasks at a flow rate of 40 mL/min. Various aging times (12,24, and 72 h) were studied. Headspace vapors from carpet were collected using sorbent glass tubes, which contained a glass wool to trap aerosols and a two-section sorbent bed (100 mg and 20 mg) of XAD-2 resin to capture vapors.…”

“…Lipofuscin activates the intracellular production of reactive oxygen species (ROS), which further damages RPE cells. Among other molecules, N-retinylidene-N-retinylethanolamine (A2E) is the major component of lipofuscin from RPE, which is a by-product of the visual cycle 24 . Studies have shown that A2E is the main component of lipofuscin and can damage RPE cell through initiating lysosomal membrane disintegration, induce ROS generation, and promote AMD 25 .…”

Bilberry anthocyanin-rich extract protects against retinal photooxidative damage via activation of HO-1 and inhibition of NF-κB

“…Excessive visible light exposure can damage the RPE cells and photoreceptors, which leads to macular degeneration Wang et al, 2018). During RPE cells phagocytose the outer segments, N-retinylidene-N-retinylethanolamine (A2E) is generated, which can accumulate and result in lipofuscin formation in the RPE cells (Sparrow, 2016).…”