Establishment of In Vitro FUS-Associated Familial Amyotrophic Lateral Sclerosis Model Using Human Induced Pluripotent Stem Cells

Stem Cell Reports. 2016 Apr 12;6(4):496-510. doi: 10.1016/j.stemcr.2016.02.011. Epub 2016 Mar 17.


Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disorder. Although its neuropathology is well understood, the cellular and molecular mechanisms are yet to be elucidated due to limitations in the currently available human genetic data. In this study, we generated induced pluripotent stem cells (iPSC) from two familial ALS (FALS) patients with a missense mutation in the fused-in sarcoma (FUS) gene carrying the heterozygous FUS H517D mutation, and isogenic iPSCs with the homozygous FUS H517D mutation by genome editing technology. These cell-derived motor neurons mimicked several neurodegenerative phenotypes including mis-localization of FUS into cytosolic and stress granules under stress conditions, and cellular vulnerability. Moreover, exon array analysis using motor neuron precursor cells (MPCs) combined with CLIP-seq datasets revealed aberrant gene expression and/or splicing pattern in FALS MPCs. These results suggest that iPSC-derived motor neurons are a useful tool for analyzing the pathogenesis of human motor neuron disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Base Sequence
  • Cell Differentiation / genetics*
  • Cells, Cultured
  • Cytosol / metabolism
  • Family Health
  • Female
  • Gene Editing
  • Gene Expression Profiling / methods
  • Heterozygote
  • Homozygote
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • Male
  • Microscopy, Fluorescence
  • Models, Genetic
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Mutation, Missense*
  • Pedigree
  • RNA-Binding Protein FUS / genetics*
  • RNA-Binding Protein FUS / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Young Adult


  • FUS protein, human
  • RNA-Binding Protein FUS