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Cell Rep. 2015 Jul 14;12(2):335-45. doi: 10.1016/j.celrep.2015.06.019. Epub 2015 Jul 2.

The Regulatory Machinery of Neurodegeneration in In Vitro Models of Amyotrophic Lateral Sclerosis.

Author information

1
Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA; Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience 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, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA.
3
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
4
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Program in Pathobiology and Molecular Medicine, Columbia University, New York, NY 10032, USA.
5
Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA; Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience 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 and Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, Columbia University, New York, NY 10032, USA.
6
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, USA. Electronic address: califano@c2b2.columbia.edu.
7
Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA; Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Program in Pathobiology and Molecular Medicine, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA. Electronic address: sp30@columbia.edu.

Abstract

Neurodegenerative phenotypes reflect complex, time-dependent molecular processes whose elucidation may reveal neuronal class-specific therapeutic targets. The current focus in neurodegeneration has been on individual genes and pathways. In contrast, we assembled a genome-wide regulatory model (henceforth, "interactome"), whose unbiased interrogation revealed 23 candidate causal master regulators of neurodegeneration in an in vitro model of amyotrophic lateral sclerosis (ALS), characterized by a loss of spinal motor neurons (MNs). Of these, eight were confirmed as specific MN death drivers in our model of familial ALS, including NF-κB, which has long been considered a pro-survival factor. Through an extensive array of molecular, pharmacological, and biochemical approaches, we have confirmed that neuronal NF-κB drives the degeneration of MNs in both familial and sporadic models of ALS, thus providing proof of principle that regulatory network analysis is a valuable tool for studying cell-specific mechanisms of neurodegeneration.

PMID:
26146077
PMCID:
PMC4646662
DOI:
10.1016/j.celrep.2015.06.019
[Indexed for MEDLINE]
Free PMC Article

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