The Regulatory Machinery of Neurodegeneration in In Vitro Models of Amyotrophic Lateral Sclerosis
Burcin Ikiz,
Mariano J. Alvarez,
Diane B. Ré,
Virginia Le Verche,
Kristin Politi,
Francesco Lotti,
Sudarshan Phani,
Radhika Pradhan,
Changhao Yu,
Gist F. Croft,
Arnaud Jacquier,
Christopher E. Henderson,
Andrea Califano,
Serge Przedborski
Affiliations
Burcin Ikiz
Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA
Mariano J. Alvarez
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Diane B. Ré
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Virginia Le Verche
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Kristin Politi
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Francesco Lotti
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Sudarshan Phani
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Radhika Pradhan
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Changhao Yu
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Gist F. Croft
Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA
Arnaud Jacquier
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Christopher E. Henderson
Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA
Andrea Califano
Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative, Columbia University, New York, NY 10032, USA
Serge Przedborski
Program in Neurobiology and Behavior, Columbia University, New York, NY 10032, USA
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.
