Expression of the ALS-causing variant hSOD1(G93A) leads to an impaired integrity and altered regulation of claudin-5 expression in an in vitro blood-spinal cord barrier model

J Cereb Blood Flow Metab. 2015 Jul;35(7):1112-21. doi: 10.1038/jcbfm.2015.57. Epub 2015 Apr 8.


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to the loss of primary and secondary motor neurons. Mutations in the Cu/Zn-superoxide dismutase (SOD1) gene are associated with familial ALS and to date numerous hypotheses for ALS pathology exist including impairment of the blood-spinal cord barrier. In transgenic mice carrying mutated SOD1 genes, a disrupted blood-spinal cord barrier as well as decreased levels of tight junction (TJ) proteins ZO-1, occludin, and claudin-5 were detected. Here, we examined TJ protein levels and barrier function of primary blood-spinal cord barrier endothelial cells of presymptomatic hSOD1(G93A) mice and bEnd.3 cells stably expressing hSOD1(G93A). In both cellular systems, we observed reduced claudin-5 levels and a decreased transendothelial resistance (TER) as well as an increased apparent permeability. Analysis of the β-catenin/AKT/forkhead box protein O1 (FoxO1) pathway and the FoxO1-regulated activity of the claudin-5 promoter revealed a repression of the claudin-5 gene expression in hSOD1(G93A) cells, which was depended on the phosphorylation status of FoxO1. These results strongly indicate that mutated SOD1 affects the expression and localization of TJ proteins leading to impaired integrity and breakdown of the blood-spinal cord barrier.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Cell Line
  • Cells, Cultured
  • Claudin-5 / analysis
  • Claudin-5 / genetics*
  • Claudin-5 / metabolism
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Gene Expression Regulation*
  • Mice
  • Mice, Transgenic
  • Signal Transduction
  • Spinal Cord / blood supply*
  • Spinal Cord / metabolism
  • Spinal Cord / pathology*
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism
  • Tight Junction Proteins / analysis
  • Tight Junction Proteins / genetics
  • Tight Junction Proteins / metabolism


  • Claudin-5
  • Tight Junction Proteins
  • SOD1 G93A protein
  • Superoxide Dismutase