Mitigation of ALS pathology by neuron-specific inhibition of nuclear factor kappa B signaling

ALS
27/05/2020

Dutta K, et al. J Neurosci 2020.

ABSTRACT

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-SRtransgene in mice expressing TDP-43A315T or TDP-43G348C miceled 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 toan 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 lifespan. The results suggest that neuronal NF-κB signaling constitutes a novel therapeutic target for ALS diseaseand related disorders with TDP-43 proteinopathy.SIGNIFICANCE STATEMENTThis study reports that neuron-specific expression of I-kappa B super-repressor mitigated behavioral and pathological changes in transgenic mouse models of ALS expressing mutant forms of either Tar DNA binding protein 43 (TDP-43) or superoxide dismutase. The results suggest that neuronal NF-κB signaling constitutes a novel therapeutic target for ALS and related disorders with TDP-43 proteinopathy.