Overexpressed wild-type superoxide dismutase 1 exhibits amyotrophic lateral sclerosis-related misfolded conformation in induced pluripotent stem cell-derived spinal motor neurons

Neuroreport. 2018 Jan 3;29(1):25-29. doi: 10.1097/WNR.0000000000000922.

Abstract

Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which motor neurons selectively degenerate. Superoxide dismutase 1 (SOD1) was found to be a causative gene of familial ALS, and mutant SOD1 transgenic mice recapitulated ALS phenotypes. Analysis of these mice showed accumulation of misfolded SOD1 protein in motor neurons. Misfolded SOD1 accumulation was found in spinal motor neurons of both familial ALS patients with the SOD1 mutation and sporadic ALS patients. However, it is unclear what condition causes wild-type SOD1 misfolding in patients without the SOD1 mutation. Here, we generated induced pluripotent stem cells from mutant SOD1 transgenic mice, wild-type SOD1 transgenic mice, and control mice, and differentiated them into spinal motor neurons to analyze misfolded SOD1 accumulation. We found that misfolded SOD1 protein was accumulated in spinal motor neurons of both mutant and wild-type SOD1 transgenic mice as detected by a specific antibody against the misfolded conformation of SOD1. These results suggest that an increased expression level of wild-type SOD1 may accelerate the ALS pathology and that our in vitro model would be a useful tool for misfolded SOD1 research.

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Embryo, Mammalian
  • Homeodomain Proteins / metabolism
  • LIM-Homeodomain Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Motor Neurons / metabolism
  • Motor Neurons / physiology*
  • Mutation / genetics*
  • Nerve Tissue Proteins / metabolism
  • Pluripotent Stem Cells / physiology*
  • Protein Folding*
  • Spinal Cord / cytology*
  • Superoxide Dismutase / genetics*
  • Time Factors
  • Transcription Factors / metabolism
  • Tubulin / metabolism

Substances

  • Homeodomain Proteins
  • LIM-Homeodomain Proteins
  • Nerve Tissue Proteins
  • Transcription Factors
  • Tubulin
  • beta3 tubulin, mouse
  • insulin gene enhancer binding protein Isl-1
  • Hb9 protein, mouse
  • SOD1 G93A protein
  • Superoxide Dismutase