Unfolded protein response in fuchs endothelial corneal dystrophy: a unifying pathogenic pathway?

Am J Ophthalmol. 2010 Feb;149(2):194-202.e2. doi: 10.1016/j.ajo.2009.09.009.


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 pathologic features 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 a sign of unfolded protein response. Normal autopsy eyes, Fuchs dystrophy corneas, and keratoconus corneas were used for immunohistochemistry. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of patient corneas for 3 unfolded protein response markers (GRP78, the alpha subunit of eukaryotic initiation factor 2, C/EBP homologous protein) and 2 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, the alpha subunit of eukaryotic initiation factor 2, C/EBP homologous protein, and caspase 9 compared with non-Fuchs dystrophy corneas (P < .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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Apoptosis*
  • Biomarkers / metabolism
  • Caspase 3 / metabolism
  • Caspase 9 / metabolism
  • Child
  • Endoplasmic Reticulum, Rough / ultrastructure*
  • Endothelium, Corneal / ultrastructure*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fuchs' Endothelial Dystrophy / metabolism
  • Fuchs' Endothelial Dystrophy / pathology*
  • Heat-Shock Proteins / metabolism
  • Humans
  • Immunohistochemistry
  • Keratoconus / metabolism
  • Keratoconus / pathology
  • Microscopy, Electron, Transmission
  • Middle Aged
  • Retrospective Studies
  • Transcription Factor CHOP / metabolism
  • Unfolded Protein Response*


  • Biomarkers
  • DDIT3 protein, human
  • Eukaryotic Initiation Factor-2
  • Heat-Shock Proteins
  • Transcription Factor CHOP
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • molecular chaperone GRP78