The Regulatory Machinery of Neurodegeneration in In Vitro Models of Amyotrophic Lateral Sclerosis
2015
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
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.
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