title: Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways.
abstract: 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.
authors.affiliation: Department of Psychiatry and Neuroscience, Research Centre of the University Hospital Centre of Quebec, Canada.
authors.forename: Vivek
authors.initials: V
authors.lastname: Swarup
authors.forename: Daniel
authors.initials: D
authors.lastname: Phaneuf
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupré
authors.forename: Susanne
authors.initials: S
authors.lastname: Petri
authors.forename: Michael
authors.initials: M
authors.lastname: Strong
authors.forename: Jasna
authors.initials: J
authors.lastname: Kriz
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Julien
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009457:Neuroglia / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000473:pathology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D054358:Withanolides / Q000494:pharmacology
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D054358:Withanolides; C009684:withaferin A
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