Trends in Neurosciences
NF-kB: a crucial transcription factor for glial and neuronal cell function
Section snippets
NF-kB as a signal transducer
In unstimulated cells NF-kB exists in a latent form, complexed to an inhibitory protein, termed IkB. As shown in Fig. 1, upon activation by a wide range of extracellular agents, IkB is phosphorylated by an, as yet unknown, protein kinase. It is then ubiquitinated and is degraded by the proteasome. This allows NF-kB to translocate to the nucleus where it binds to the kB consensus sequence (the commonest form of which is GGGACTTTCC), generally leading to an increase in the expression of the
NF-kB as a signal in the brain during inflammation, injury and viral infection
Much of the work described above was carried out on immune or connective-tissue cells. However, it has become evident that a range of stimuli will activate NF-kB in brain-derived cells, and a large number of NF-kB-regulated genes become induced. These are summarized in Fig. 1. Relatively early in the study of the field (1989), a protein complex was described in grey matter and cultured cerebellar neurones that recognized the NF-kB binding motif[7]. Several reports then appeared that described
NF-kB as a signal in synaptic transmission and neuronal plasticity
As mentioned above, in a model of seizure increases in NF-kB occur in the cortex and hippocampus[19]. Other studies on neuronal excitation indicate that NF-kB might be regulated during synaptic transmission. Fig. 2 describes the main features of the NF-kB activities that have been detected in neurones: constitutive NF-kB activity free of IkB in the nucleus; inducible NF-kB activity in the cytoplasm; and inducible activity in the synapse. Using DNA-binding assays, inducible forms have been found
NF-kB as a signal in neuronal development
Along with the potential role of NF-kB in neuronal function in the adult brain, it has been indicated in a series of recent papers that NF-kB might be important for neuronal development. Part of the inspiration for this work was the known role of dorsal, a homologue of NF-kB, in Drosophila development. A high-molecular-weight complex (110–115kDa) with NF-kB binding activity was found to be present in nuclei of young rats and mice (up to postnatal day 2); the ac- tivity was highest in developing
NF-kB as an important signal in neurodegenerative diseases
Evidence is accumulating for a role for NF-kB in neurodegenerative disease. Recently it has been reported that the neurotoxic peptide Ab< which is deposited in plaques of Alzheimer's disease patients, can activate NF-kB in neuroblastoma cells[50] and in cerebellar granule cells[51]. This activation is dependent on the formation of reactive oxygen intermediates. A similar mechanism has been shown to be operative in nanomolar concentrations in the activation of NF-kB via glycated tau proteins[52]
Concluding remarks
It is four years since the first definitive description of NF-kB in the CNS. This factor clearly has a potentially determining role in several processes. An obvious goal for future studies will be to determine whether activation of NF-kB is important for neuroprotection or neurodegeneration. This might depend on the particular system under investigation and the NF-kB subunits that become activated. The identification of target genes for NF-kB in the CNS might help to resolve this question. This
Acknowledgements
This work was supported in part by grants to L.O.N. from the Irish Health Research Board and the Irish Science and Technology Agency Forbairt and the European Commission, and to C.K. from the Deutsche Forschungsgemeinschaft, Volkswagen-Stiftung and the European Community. C.K. also thanks B. Kaltschmidt for invaluable contributions.
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