Impairment of visual function and retinal ER stress activation in Wfs1-deficient mice

PLoS One. 2014 May 13;9(5):e97222. doi: 10.1371/journal.pone.0097222. eCollection 2014.

Abstract

Wolfram syndrome is an early onset genetic disease (1/180,000) featuring diabetes mellitus and optic neuropathy, associated to mutations in the WFS1 gene. Wfs1-/- mouse model shows pancreatic beta cell atrophy, but its visual performance has not been investigated, prompting us to study its visual function and histopathology of the retina and optic nerve. Electroretinogram and visual evoked potentials (VEPs) were performed in Wfs1-/- and Wfs1+/+ mice at 3, 6, 9 and 12 months of age. Fundi were pictured with Micron III apparatus. Retinal ganglion cell (RGC) abundance was determined from Brn3a immunolabeling of retinal sections. RGC axonal loss was quantified by electron microscopy in transversal optic nerve sections. Endoplasmic reticulum stress was assessed using immunoglobulin binding protein (BiP), protein disulfide isomerase (PDI) and inositol-requiring enzyme 1 alpha (Ire1α) markers. Electroretinograms amplitudes were slightly reduced and latencies increased with time in Wfs1-/- mice. Similarly, VEPs showed decreased N+P amplitudes and increased N-wave latency. Analysis of unfolded protein response signaling revealed an activation of endoplasmic reticulum stress in Wfs1-/- mutant mouse retinas. Altogether, progressive VEPs alterations with minimal neuronal cell loss suggest functional alteration of the action potential in the Wfs1-/- optic pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Blotting, Western
  • Contrast Sensitivity / genetics*
  • Contrast Sensitivity / physiology
  • DNA Primers / genetics
  • Electroretinography
  • Endoplasmic Reticulum Stress / physiology*
  • Endoribonucleases / metabolism
  • Evoked Potentials, Visual / physiology
  • Heat-Shock Proteins / metabolism
  • Immunohistochemistry
  • Membrane Proteins / deficiency*
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Polymerase Chain Reaction
  • Protein Disulfide-Isomerases / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Retina / metabolism
  • Retina / physiopathology*
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / physiology
  • Unfolded Protein Response / physiology
  • Visual Acuity / genetics*
  • Visual Acuity / physiology

Substances

  • DNA Primers
  • Heat-Shock Proteins
  • Membrane Proteins
  • wolframin protein
  • Ern1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • Protein Disulfide-Isomerases
  • molecular chaperone GRP78

Grant support

This work was supported by private foundations (French association against Myopathies (AFM), Retina France, Association du Syndrome de Wolfram, Fondation de France), the French Ministry for National Education and Inserm. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.