Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability

Nat Commun. 2015 Jan 12;6:5999. doi: 10.1038/ncomms6999.

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which a greater understanding of early disease mechanisms is needed to reveal novel therapeutic targets. We report the use of human induced pluripotent stem cell (iPSC)-derived motoneurons (MNs) to study the pathophysiology of ALS. We demonstrate that MNs derived from iPSCs obtained from healthy individuals or patients harbouring TARDBP or C9ORF72 ALS-causing mutations are able to develop appropriate physiological properties. However, patient iPSC-derived MNs, independent of genotype, display an initial hyperexcitability followed by progressive loss of action potential output and synaptic activity. This loss of functional output reflects a progressive decrease in voltage-activated Na(+) and K(+) currents, which occurs in the absence of overt changes in cell viability. These data implicate early dysfunction or loss of ion channels as a convergent point that may contribute to the initiation of downstream degenerative pathways that ultimately lead to MN loss in ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Amyotrophic Lateral Sclerosis / genetics
  • C9orf72 Protein
  • Cell Line
  • Cell Survival
  • DNA-Binding Proteins / genetics*
  • Female
  • Genotype
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Male
  • Motor Neurons / pathology
  • Mutation*
  • Open Reading Frames*
  • Patch-Clamp Techniques
  • Potassium / chemistry
  • Proteins / genetics*
  • Sodium / chemistry

Substances

  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • Proteins
  • TARDBP protein, human
  • Sodium
  • Potassium