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Publication Detail

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

Authors: Ikiz, Burcin; Alvarez, Mariano J; Ré, Diane B; Le Verche, Virginia; Politi, Kristin; Lotti, Francesco; Phani, Sudarshan; Pradhan, Radhika; Yu, Changhao; Croft, Gist F; Jacquier, Arnaud; Henderson, Christopher E; Califano, Andrea; Przedborski, Serge

Published In Cell Rep, (2015 Jul 14)

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.

PubMed ID: 26146077 Exiting the NIEHS site

MeSH Terms: Amyotrophic Lateral Sclerosis/metabolism; Amyotrophic Lateral Sclerosis/pathology; Animals; Apoptosis/drug effects; Astrocytes/cytology; Astrocytes/metabolism; Cells, Cultured; Culture Media, Conditioned/pharmacology; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Humans; Mice; Mice, Transgenic; Models, Biological*; Motor Neurons/cytology; Motor Neurons/drug effects; Motor Neurons/metabolism*; Mutation; NF-kappa B/metabolism*; RNA Interference; RNA, Small Interfering/metabolism; Superoxide Dismutase/antagonists & inhibitors; Superoxide Dismutase/genetics; Superoxide Dismutase/metabolism; Transcription Factors/genetics; Transcription Factors/metabolism; Transcriptome/drug effects

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