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

Diane B Re; Virginia Le Verche; Changhao Yu; Mackenzie W Amoroso; Kristin A Politi; Sudarshan Phani; Burcin Ikiz; Lucas Hoffmann; Martijn Koolen; Tetsuya Nagata; Dimitra Papadimitriou; Peter Nagy; Hiroshi Mitsumoto; Shingo Kariya; Hynek Wichterle; Christopher E Henderson; Serge Przedborski

doi:10.1016/j.neuron.2014.01.011

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.

Authors

Diane B Re¹, Virginia Le Verche¹, Changhao Yu¹, Mackenzie W Amoroso², Kristin A Politi¹, Sudarshan Phani¹, Burcin Ikiz¹, Lucas Hoffmann³, Martijn Koolen⁴, Tetsuya Nagata¹, Dimitra Papadimitriou¹, Peter Nagy¹, Hiroshi Mitsumoto⁵, Shingo Kariya¹, Hynek Wichterle⁶, Christopher E Henderson⁷, Serge Przedborski⁸

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.

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.

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding