title: The Regulatory Machinery of Neurodegeneration in In Vitro Models of Amyotrophic Lateral Sclerosis.
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.
authors.affiliation: 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.
authors.forename: Burcin
authors.initials: B
authors.lastname: Ikiz
authors.affiliation: 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.
authors.forename: Mariano J
authors.initials: MJ
authors.lastname: Alvarez
authors.affiliation: 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.
authors.forename: Diane B
authors.initials: DB
authors.lastname: Ré
authors.affiliation: 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.
authors.forename: Virginia
authors.initials: V
authors.lastname: Le Verche
authors.affiliation: 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.
authors.forename: Kristin
authors.initials: K
authors.lastname: Politi
authors.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lotti
authors.affiliation: 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.
authors.forename: Sudarshan
authors.initials: S
authors.lastname: Phani
authors.affiliation: 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.
authors.forename: Radhika
authors.initials: R
authors.lastname: Pradhan
authors.affiliation: 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.
authors.forename: Changhao
authors.initials: C
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Gist F
authors.initials: GF
authors.lastname: Croft
authors.affiliation: 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.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jacquier
authors.affiliation: 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.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Henderson
authors.affiliation: 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.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: 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.
authors.forename: Serge
authors.initials: S
authors.lastname: Przedborski
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects
chemical_list: D017077:Culture Media, Conditioned; D018398:Homeodomain Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014157:Transcription Factors; C084059:Hb9 protein, mouse; D013482:Superoxide Dismutase