Differential expression of NEAT1 in the corneal endothelium increases susceptibility to oxidative stress in Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a disease that targets the corneal endothelium (CE), causing cell loss and subsequent vision impairment. The cause of this spatial discrepancy remains a mystery, but oxidative stress has been identified as a significant factor. CECs, which are non-proliferative, are especially vulnerable to damage from reactive oxygen species (ROS), high metabolic activity, and ultraviolet DNA damage.

In this study, researchers exposed ex-vivo corneal samples to hydrogen peroxide (H2O2) and observed a higher cell death rate in the central CE compared to the peripheral CE. To probe for the reasons behind this discrepancy, the team conducted bulk RNA sequencing on the central and peripheral CE regions from both FECD and normal cadaveric donors.

They found that many genes related to collagen and extracellular matrix were more prominent in the central CE than the peripheral CE, as well as between normal and FECD CE. Notably, they discovered that a long non-coding RNA (lncRNA) called NEAT1 exhibited reduced expression in the central CE when compared to the peripheral CE, and was also lower in FECD compared to normal CE.

Through further investigation using corneal endothelial cell lines and specimens from FECD patients and normal cadavers, they discovered that FECD showed decreased NEAT1 expression and heightened susceptibility to H2O2-induced oxidative stress. The study indicates that NEAT1 knockdown in both normal and FECD cells exacerbates H2O2-mediated oxidative stress, while NEAT1 overexpression provides protection to FECD cells.

The researchers conclude that the reduced expression of NEAT1 in the central CE is a potential contributor to oxidative stress-related cell death in FECD. This discovery sheds new light on FECD pathogenesis and helps explain why the disease predominantly affects the central CE. The authors propose that targeting NEAT1 signaling with antioxidants may pave the way for novel therapeutics aimed at preventing FECD pathogenesis.