A novel proteotoxic stress‐associated mechanism for macular corneal dystrophy

AbstractPurpose Macular corneal dystrophy is a rare autosomal recessive eye disease primarily affecting the corneal stroma. Abnormal deposits have been observed intra‐ and extracellularly in the stromal layer. In addition to the stromal keratocytes and corneal lamellae, deposits are also present in the basal epithelial cells, endothelial cells and Descemet's membrane. Misfolded proteins have a tendency to gather into aggregating deposits. We studied the interaction of molecular chaperones and proteasomal clearance in macular dystrophy human samples and in human corneal HCE‐2 epithelial cells in this disease.Methods Seven cases of macular dystrophy and 5 normal human corneal buttons were collected during corneal transplantation. Fluorescent immunohistochemistry on human donor corneal button was used to verify the spatial distribution pattern of selected Hsp70, SQSTM1/p62 and ubiquitin molecules, respectively. The expression level of these proteins were analysed in HCE‐2 cells using western blotting and transmission electron microscopy, respectively.Results Highly elevated Hsp70, SQSTM1/p62 and ubiquitin protein conjugates were observed in intracellular space of the epithelial cells in macular dystrophies. All the studied proteins were also highly elevated under proteasome inhibition in human corneal epithelial HCE‐2 cells in cell cultures.Conclusion We report a novel proteostatic regulatory mechanism that connects the molecular chaperone and proteasomal clearance system with the pathogenesis of macular corneal dystrophy.