Unfolded Protein Response in Fuchs Endothelial Corneal Dystrophy: A Unifying Pathogenic Pathway?

Abstract

Purpose To assess for activation of the unfolded protein response in corneal endothelium of Fuchs endothelial corneal dystrophy patients. Design Retrospective comparative case series of laboratory specimens Methods Corneal specimens of patients with Fuchs dystrophy and controls with corneal pathologies other than Fuchs dystrophy were evaluated by transmission electron microscopy (TEM) to evaluate for structural changes of the rough endoplasmic reticulum in corneal endothelium. TEM images were evaluated for alterations of rough endoplasmic reticulum as sign of unfolded protein response. Normal autopsy eyes, Fuchs dystrophy, and keratoconus corneas were used for immunohistochemistry. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of patient corneas for three unfolded protein response markers (GRP78, phospho-eIF2α, CHOP) and two apoptosis markers (Caspase 3 and 9). Immunohistochemistry signal quantitation of corneal endothelium for evaluation of marker expression was performed using automated software. Corneal sections were assessed quantitatively for levels of immunohistochemistry marker expression. Results TEM showed enlargement of rough endoplasmic reticulum in corneal endothelium of all Fuchs dystrophy specimens. Immunohistochemistry quantitation demonstrated a significant increase in mean signal in corneal endothelium from Fuchs dystrophy patients for markers GRP78, phospho-eIF2α, CHOP and caspase 9, compared with non- Fuchs dystrophy corneas (p < 0.05). Conclusions Results of both TEM and immunohistochemistry indicate activation of unfolded protein response in Fuchs dystrophy. Unfolded protein response activation leads to endothelial cell apoptosis in Fuchs dystrophy and may play a central pathogenic role in this disease.

Involvement of ZEB1 and Snail1 in excessive production of extracellular matrix in Fuchs endothelial corneal dystrophy

“…17 The thickened Descemet's membrane and excrescences comprise several ECMs such as collagen types I, IV, and VIII; fibronection; and laminin-these were considered to be secreted by affected CECs. 14 Since small sample size obtained from FECD patients is an obstacle for researchers, 11 we established an in vitro cellular model of FECD by immortalization of the CECs received from late-onset FECD patients. The data presented in this study identified potential overexpressed ECM proteins, which include collagen type I and fibronectin at both mRNA and protein levels and probably contribute to the excessive ECM deposition found in Descemet's membrane in FECD.…”

“…In this study, we investigated the molecular mechanisms of excessive ECM production as a possible cause of ER stress 11 in CECs in FECD. For this purpose, we established an FECD cellular in vitro model using immortalized cell lines derived from FECD and control patients.…”

Polymorphisms of the Apoptosis-Related FAS and FAS Ligand Genes in Keratoconus and Fuchs Endothelial Corneal Dystrophy

“…Oxidative stress and apoptosis are reported to play a role in the development of FECD particularly in regard to accelerated corneal endothelial cell loss (Borderie et al 2000;Li et al 2001;Buddi et al 2002;Szentmáry et al 2005;Engler et al 2010;Jurkunas et al 2010;Azizi et al 2011). This may be in part due to chronic ultraviolet (UV) light exposure (Inoki et al 2004).…”

“…Both association and linkage studies showed that a polymorphism in the transcription factor 4 (TCF4) gene was associated with FECD (Baratz et al 2010;Li et al 2011). Apoptosis was shown to be involved in the pathogenesis of KC and FECD (Mohan et al 1997;Cho et al 1999;Kim et al 1999;Borderie et al 2000;Li et al 2001;Kaldawy et al 2002;Gottsch et al 2003;Szentmáry et al 2005;Joyce et al 2009;Engler et al 2010;Jurkunas et al 2010). It was also shown that the FAS/FASLG system is expressed in the cornea and might have important functions in normal corneal physiology and in the pathophysiology of corneal diseases, including modulation of keratocyte apoptosis after epithelial injury (Wilson et al 1996).…”

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

“…However, this theory would agree with aberrant protein expression, which is one of the consequences of oxidative stress-induced damage. 51 Wound healing patterns of the normal and FECD corneal endothelium Until recently it was thought (as endothelial cells were believed to have no regenerative potential) that when a corneal cell is 'lost', it induces a wound healing response where the defect of the lost cell is covered by an adjacent endothelial cell through migration and elongation. 13 However, a recent study by He et al, 40 suggested that the corneal periphery contains a reservoir of stem-like cells that replace damaged or dead endothelium by continuous centripetal migration patterns (Figures 1b and c).…”