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

The discovery of key mediators of neurodegenerative phenotypes, especially prior to neurons becoming committed to die, has proven both complex and inefficient. In contrast to the current focus on identifying individual genes and pathways, a new study by Serge Przedborski and Andrea Califano, along with first co-authors Burcin Ikiz and Mariano Alvarez and colleagues, utilized an extensive array of molecular, pharmacological, and biochemical approaches to assemble and interrogate a “brain-specific model of transcriptional regulation with genome-wide disease signatures,” in an in vitro model of amyotrophic lateral sclerosis (ALS). Published online this week in Cell Reports, their unbiased, systems biology analysis of this mouse brain “interactome” (see figure right) was successful in identifying a “comprehensive set of regulatory genes driving ES-MN (embryonic stem cell–derived motor neuron) degeneration in a highly relevant cell model of ALS, including 14 causal effector genes as well as their transcriptional programs.” This study suggests that regulatory network analysis may be a more powerful approach than more traditional assays of individual genes to unravel mechanisms of neurodegeneration and therapeutic targets for the treatment of these dreadful neurological disorders. This work is the fruit of a multidisciplinary collaboration between Columbia’s Center for Motor Neuron Biology and Disease and the Department of System Biology, as well as the Columbia Stem Cell Initiative and Columbia Translational Neuroscience Initiative (CTNI).