Necroptosis drives motor neuron death in models of both sporadic and familial ALS

Neuron. 2014 Mar 5;81(5):1001-1008. doi: 10.1016/j.neuron.2014.01.011. Epub 2014 Feb 6.


Most cases of neurodegenerative diseases are sporadic, hindering the use of genetic mouse models to analyze disease mechanisms. Focusing on the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS), we therefore devised a fully humanized coculture model composed of human adult primary sporadic ALS (sALS) astrocytes and human embryonic stem-cell-derived MNs. The model reproduces the cardinal features of human ALS: sALS astrocytes, but not those from control patients, trigger selective death of MNs. The mechanisms underlying this non-cell-autonomous toxicity were investigated in both astrocytes and MNs. Although causal in familial ALS (fALS), SOD1 does not contribute to the toxicity of sALS astrocytes. Death of MNs triggered by either sALS or fALS astrocytes occurs through necroptosis, a form of programmed necrosis involving receptor-interacting protein 1 and the mixed lineage kinase domain-like protein. The necroptotic pathway therefore constitutes a potential therapeutic target for this incurable disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Astrocytes / cytology*
  • Cell Communication / physiology*
  • Cell Death / physiology*
  • Coculture Techniques
  • DNA-Binding Proteins / physiology
  • Embryonic Stem Cells / cytology
  • Fibroblasts / cytology
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • Motor Neurons / cytology*
  • Necrosis / pathology
  • Primary Cell Culture
  • Protein Kinases / physiology
  • Receptor-Interacting Protein Serine-Threonine Kinases / physiology
  • Spinal Cord / cytology
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / physiology
  • Superoxide Dismutase-1


  • DNA-Binding Proteins
  • SOD1 protein, human
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • MLKL protein, human
  • Protein Kinases
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases