title: Necroptosis drives motor neuron death in models of both sporadic and familial ALS.
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.
authors: Center 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.
authors: Diane B
authors: DB
authors: Re
authors: Center 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.
authors: Virginia
authors: V
authors: Le Verche
authors: Center 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.
authors: Changhao
authors: C
authors: Yu
authors: Center 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.
authors: Mackenzie W
authors: MW
authors: Amoroso
authors: Center 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.
authors: Kristin A
authors: KA
authors: Politi
authors: Center 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.
authors: Sudarshan
authors: S
authors: Phani
authors: Center 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.
authors: Burcin
authors: B
authors: Ikiz
authors: Center for Motor Neuron Biology and Disease, the Columbia Translational Neuroscience Initiative, and the Columbia Stem Cell Initiative, Columbia University, New York, NY 10032, USA.
authors: Lucas
authors: L
authors: Hoffmann
authors: Center 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.
authors: Martijn
authors: M
authors: Koolen
authors: Center 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.
authors: Tetsuya
authors: T
authors: Nagata
authors: Center 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.
authors: Dimitra
authors: D
authors: Papadimitriou
authors: Center 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.
authors: Peter
authors: P
authors: Nagy
authors: Center 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.
authors: Hiroshi
authors: H
authors: Mitsumoto
authors: Center 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.
authors: Shingo
authors: S
authors: Kariya
authors: Center 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.
authors: Hynek
authors: H
authors: Wichterle
authors: Center 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.
authors: Christopher E
authors: CE
authors: Henderson
authors: Center 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.
authors: Serge
authors: S
authors: Przedborski
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D002450:Cell Communication / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000166:cytology*; D009336:Necrosis / Q000473:pathology; D061251:Primary Cell Culture; D011494:Protein Kinases / Q000502:physiology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology; D000072105:Superoxide Dismutase-1
chemical_list: D004268:DNA-Binding Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C570693:MLKL protein, human; D011494:Protein Kinases; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases