| First Author | Dutta K | Year | 2020 |
| Journal | J Neurosci | Volume | 40 |
| Issue | 26 | Pages | 5137-5154 |
| PubMed ID | 32457070 | Mgi Jnum | J:294368 |
| Mgi Id | MGI:6437666 | Doi | 10.1523/JNEUROSCI.0536-20.2020 |
| Citation | Dutta K, et al. (2020) Mitigation of ALS Pathology by Neuron-Specific Inhibition of Nuclear Factor Kappa B Signaling. J Neurosci 40(26):5137-5154 |
| abstractText | To investigate the role of neuronal NF-kappaB activity in pathogenesis of amyotrophic lateral sclerosis (ALS), we generated transgenic mice with neuron-specific expression of a super-repressor form of the NF-kappaB inhibitor (IkappaBalpha-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 IkappaBalpha-SR transgene in mice expressing TDP-43(A315T) or TDP-43(G348C) mice led to a decrease in cytoplasmic to nuclear ratio of human TDP-43. The mitigation of TDP-43 neuropathology by IkappaBalpha-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-kappaB activity in SOD1(G93A) mice also resulted in neuroprotection with reduction of misfolded SOD1 levels and significant extension of life span. The results suggest that neuronal NF-kappaB 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 IkappaB 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-kappaB signaling constitutes a novel therapeutic target for amyotrophic lateral sclerosis and related disorders with Tar DNA-binding protein 43 proteinopathy. |
