DNA damage and repair in Fuchs endothelial corneal dystrophy

Abstract

Fuchs endothelial corneal dystrophy (FECD) is a slowly progressive eye disease leading to blindness, mostly affecting people above 40 years old. The only known method of curing FECD is corneal transplantation. The disease is characterized by the presence of extracellular deposits called “cornea guttata”, apoptosis of corneal endothelial cells, dysfunction of Descement’s membrane and corneal edema. Oxidative stress is suggested to play a role in FECD pathogenesis. Reactive oxygen species produced during the stress may damage biomolecules, including DNA. In the present study we evaluated the extent of endogenous DNA damage, including oxidatively modified DNA bases, and damage induced by hydrogen peroxide as well as the kinetics of DNA repair in peripheral blood mononuclear cells of 50 patients with FECD and 43 age-matched controls without visual disturbances. To quantify DNA damage and repair we used the alkaline comet assay technique with the enzymes recognizing oxidative DNA damage, hOGG1 and EndoIII. We did not observe differences in the extent of endogenous and hydrogen peroxide-induced DNA damage between FECD patients and controls. However, we found a lower efficacy of DNA repair in FECD patients as compared with control individuals. The results obtained suggest that the lowering of the DNA repair capacity may be one of the mechanisms underlying the role of oxidative stress in the FECD pathology.

Oxidative Stress in the Pathogenesis of Keratoconus and Fuchs Endothelial Corneal Dystrophy

“…Increased oxidative stress in FECD cornea may contribute to endothelial oxidative DNA damage, morphological modification and apoptosis. We showed that FECD patients displayed greater levels of oxidative DNA lesions compared with age- and sex-matched controls [76]. It was also shown that the level of 8-hydroxy-2′-deoxyguanosine, a marker of oxidative DNA damage, was increased in FECD endothelium [13].…”

What does the future hold for the treatment of Fuchs endothelial dystrophy; will ‘keratoplasty’ still be a valid procedure?

“…44 Interestingly, several authors have found evidence of increased apoptosis having a role in endothelial cell loss, as observed in FECD. 46,47 Furthermore, it was shown that the defense mechanism of FECD endothelium against oxidative stress-induced damage is impaired when compared with normal cells, 39,45,48,49 which is supported by the observed significant higher levels of (baseline) oxidative stressinduced damage, 43,45,48 and changes in endothelial cell morphology characteristic for oxidative stress. 50 These data suggest that chronic oxidative stress contributes to the pathophysiology of FECD, and that the decreased defense system renders FECD endothelial cells even more susceptible to oxidative stress-induced damage than normal cells already are.…”

“…[40][41][42] Corneal endothelial cells are thought to be especially vulnerable to oxidative stress-induced damage because they do not proliferate and have a high level of metabolic activity owing to their pump function. 39,43 Fortunately, these cells have several defense mechanisms against the detrimental effects of oxidative stress, 44,45 thereby reducing damage and promoting cell survival. However, if oxidative stress persists, the defense mechanisms fail, thereby allowing the cell to accumulate damage.…”

N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy

“…Fuchs endothelial corneal dystrophy (FECD) is a slowly progressive eye disease leading to corneal vision loss, mostly affecting people above 40 years old (Czarny et al, 2013). The only definitive treatment of FECD is corneal transplantation (Czarny et al, 2013; Rose et al, 2009).…”

“…The only definitive treatment of FECD is corneal transplantation (Czarny et al, 2013; Rose et al, 2009). Endoplasmic reticulum (ER) and oxidative stress contribute to the pathogenesis of FECD (Azizi et al, 2011; Engler et al, 2010).…”