title: Forebrain-specific neuronal inhibition of nuclear factor-kappaB activity leads to loss of neuroprotection.
abstract: The transcription factor Rel/nuclear factor (NF)-kappaB is known for its fundamental role in regulating immune and inflammatory responses. In the brain, constitutive NF-kappaB activity has been detected exclusively in neurons, and a large diversity of stimuli have been reported to induce NF-kappaB activity. Yet the function of this transcription factor in the nervous system remains unclear, and its role in neuroprotection or neurodegeneration is open to debate. Recently it was suggested that kappaB-driven gene expression in neurons is controlled by Sp1-like factors. To clarify such controversy, we have characterized here a novel mouse model in which the entire NF-kappaB-dependent transcriptional response is abolished in the forebrain. Calcium-calmodulin-dependent kinase II alpha promoter-driven tetracycline transactivator was used for regulated expression of a transdominant negative mutant of inhibitor kappaBalpha (super-repressor) together with a green fluorescent protein tracer. Inhibition of expression of a kappaB-dependent lacZ transgene was shown in triple transgenic mice, which correlated with the loss of kappaB-specific DNA binding. In transgenic organotypic hippocampal slice cultures, expression of the super-repressor led to strong cell death after neurotoxic insults. These data demonstrate for the first time that neuron-restricted ablation of NF-kappaB-driven gene expression increases neurodegeneration. This might lead to the path for new treatments of neurodegenerative diseases.
authors.affiliation: Unité de Biologie Moléculaire de l'Expression Génique, Centre National de la Recherche Scientifique 2582, Institut Pasteur, Paris Cedex 15, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Fridmacher
authors.forename: Barbara
authors.initials: B
authors.lastname: Kaltschmidt
authors.forename: Bertrand
authors.initials: B
authors.lastname: Goudeau
authors.forename: Delphine
authors.initials: D
authors.lastname: Ndiaye
authors.forename: Francesco Mattia
authors.initials: FM
authors.lastname: Rossi
authors.forename: Julia
authors.initials: J
authors.lastname: Pfeiffer
authors.forename: Christian
authors.initials: C
authors.lastname: Kaltschmidt
authors.forename: Alain
authors.initials: A
authors.lastname: Israël
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mémet
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics*; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism*; D019076:Transgenes
chemical_list: D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D008164:Luminescent Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009498:Neurotoxins; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D049452:Green Fluorescent Proteins; C517657:CAMK2A protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517671:Camk2a protein, mouse; D007608:Kainic Acid