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Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways.

Publication Type:

Journal Article

Source:

J Exp Med, Volume 208, Issue 12, p.2429-47 (2011)

Keywords:

Amyotrophic Lateral Sclerosis, Analysis of Variance, Animals, Blotting, Western, DNA Primers, DNA-Binding Proteins, Electrophoretic Mobility Shift Assay, Enzyme-Linked Immunosorbent Assay, Humans, Immunoprecipitation, Mass Spectrometry, Mice, Mice, Transgenic, Microscopy, Fluorescence, Neuroglia, Neuromuscular Junction, Neurons, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Signal Transduction, Spinal Cord, Transcription Factor RelA, Transgenes, Withanolides

Abstract:

<p>TDP-43 (TAR DNA-binding protein 43) inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). In this study, we report that TDP-43 and nuclear factor κB (NF-κB) p65 messenger RNA and protein expression is higher in spinal cords in ALS patients than healthy individuals. TDP-43 interacts with and colocalizes with p65 in glial and neuronal cells from ALS patients and mice expressing wild-type and mutant TDP-43 transgenes but not in cells from healthy individuals or nontransgenic mice. TDP-43 acted as a co-activator of p65, and glial cells expressing higher amounts of TDP-43 produced more proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide or reactive oxygen species. TDP-43 overexpression in neurons also increased their vulnerability to toxic mediators. Treatment of TDP-43 mice with Withaferin A, an inhibitor of NF-κB activity, reduced denervation in the neuromuscular junction and ALS disease symptoms. We propose that TDP-43 deregulation contributes to ALS pathogenesis in part by enhancing NF-κB activation and that NF-κB may constitute a therapeutic target for the disease.</p>

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