Mitigation of ALS Pathology by Neuron-Specific Inhibition of Nuclear Factor Kappa B Signaling

J Neurosci. 2020 Jun 24;40(26):5137-5154. doi: 10.1523/JNEUROSCI.0536-20.2020. Epub 2020 May 26.


To investigate the role of neuronal NF-κB activity in pathogenesis of amyotrophic lateral sclerosis (ALS), we generated transgenic mice with neuron-specific expression of a super-repressor form of the NF-κB inhibitor (IκBα-SR), which were then crossed with mice of both sexes, expressing ALS-linked gene mutants for TAR DNA-binding protein (TDP-43) and superoxide dismutase 1 (SOD1). Remarkably, neuronal expression of IκBα-SR transgene in mice expressing TDP-43A315T or TDP-43G348C mice led to a decrease in cytoplasmic to nuclear ratio of human TDP-43. The mitigation of TDP-43 neuropathology by IκBα-SR, which is likely due to an induction of autophagy, was associated with amelioration of cognitive and motor deficits as well as reduction of motor neuron loss and gliosis. Neuronal suppression of NF-κB activity in SOD1G93A mice also resulted in neuroprotection with reduction of misfolded SOD1 levels and significant extension of life span. The results suggest that neuronal NF-κB signaling constitutes a novel therapeutic target for ALS disease and related disorders with TDP-43 proteinopathy.SIGNIFICANCE STATEMENT This study reports that neuron-specific expression of IκB super-repressor mitigated behavioral and pathologic changes in transgenic mouse models of amyotrophic lateral sclerosis expressing mutant forms of either Tar DNA-binding protein 43 or superoxide dismutase. The results suggest that neuronal NF-κB signaling constitutes a novel therapeutic target for amyotrophic lateral sclerosis and related disorders with Tar DNA-binding protein 43 proteinopathy.

Keywords: IκB suppressor; NF-κB; TDP-43; amyotrophic lateral sclerosis; frontotemporal dementia; superoxide dismutase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • DNA-Binding Proteins / genetics
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • NF-KappaB Inhibitor alpha / metabolism*
  • NF-kappa B / metabolism*
  • Signal Transduction / physiology*
  • Superoxide Dismutase-1 / genetics


  • DNA-Binding Proteins
  • NF-kappa B
  • SOD1 protein, human
  • TARDBP protein, human
  • NF-KappaB Inhibitor alpha
  • Superoxide Dismutase-1

Grant support