Abstract
Nuclear Factor Kappa B (NF-κB) is a ubiquitously expressed transcription factor with key functions in a wide array of biological systems. While the role of NF-κB in processes, such as host immunity and oncogenesis has been more clearly defined, an understanding of the basic functions of NF-κB in the nervous system has lagged behind. The vast cell-type heterogeneity within the central nervous system (CNS) and the interplay between cell-type specific roles of NF-κB contributes to the complexity of understanding NF-κB functions in the brain. In this review, we will focus on the emerging understanding of cell-autonomous regulation of NF-κB signaling as well as the non-cell-autonomous functional impacts of NF-κB activation in the mammalian nervous system. We will focus on recent work which is unlocking the pleiotropic roles of NF-κB in neurons and glial cells (including astrocytes and microglia). Normal physiology as well as disorders of the CNS in which NF-κB signaling has been implicated will be discussed with reference to the lens of cell-type specific responses.
Highlights
Mammalian NF-κB functions as a dimer composed of five potential Rel/NF-κB family subunits that can be divided into two classes
The death of motor neurons could be rescued through selective NF-κB inhibition (IKKβ deficiency or dominant negative IκB (DN-IκB) expression, using colony stimulating factor receptor (CSF-1R) promoter driver which is microglia selective within the post-natal mouse brain) in microglial cells, while NF-κB inhibition in the astrocyte glial subtype was without effect [108]
NF-(kappa)B mediates amyloid beta peptide-stimulated activity of the human apolipoprotein E gene promoter in human astroglial cells A critical role of astrocyte-mediated nuclear factor-kappaB-dependent inflammation in Huntington’s disease Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor kappaB-mediated pathogenic pathways NF-kappaB activation in astrocytes drives a stage-specific beneficial neuroimmunological response in Amyotrophic lateral sclerosis (ALS) Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease
Summary
Mammalian NF-κB functions as a dimer composed of five potential Rel/NF-κB family subunits that can be divided into two classes. Effective promoters for driving cell-type selective manipulations of the NF-κB signaling pathway exist for neurons but have until very recently hampered studies of glial-specific roles, as discussed below.
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