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Neuron. 2014 Mar 5;81(5):1001-8. doi: 10.1016/j.neuron.2014.01.011. Epub 2014 Feb 6.

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

Author information

  • 1Center for Motor Neuron Biology and Disease, the Columbia Translational Neuroscience Initiative, and the Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
  • 2Center for Motor Neuron Biology and Disease, the Columbia Translational Neuroscience Initiative, and the Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, NY 10032, USA; Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA.
  • 3Center for Motor Neuron Biology and Disease, the Columbia Translational Neuroscience Initiative, and the Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA.
  • 4Center for Motor Neuron Biology and Disease, the Columbia Translational Neuroscience Initiative, and the Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Academisch Medisch Centrum, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
  • 5Center for Motor Neuron Biology and Disease, the Columbia Translational Neuroscience Initiative, and the Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA.
  • 6Center for Motor Neuron Biology and Disease, the Columbia Translational Neuroscience Initiative, and the Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Department of Neuroscience, Columbia University, New York, NY 10032, USA; Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA.
  • 7Center for Motor Neuron Biology and Disease, the Columbia Translational Neuroscience Initiative, and the Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA; Department of Neuroscience, Columbia University, New York, NY 10032, USA; Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, NY 10032, USA; Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY 10032, USA.
  • 8Center for Motor Neuron Biology and Disease, the Columbia Translational Neuroscience Initiative, and the Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA. Electronic address: sp30@columbia.edu.

Abstract

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24508385
[PubMed - indexed for MEDLINE]
PMCID:
PMC3951532
Free PMC Article
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