Endoplasmic reticulum stress is accompanied by activation of NF-κB in amyotrophic lateral sclerosis

Background: Recent studies have indicated that endoplasmic reticulum (ER) stress is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). ER stress occurs when the ER-mitochondria calcium cycle is disturbed and misfolded proteins accumulate in the ER. To cope with ER stress, cells activate the unfolded protein response (UPR). Accumulating evidence from non-neuronal cell models suggests that there is extensive cross-talk between the UPR and the NF-kappa B pathway. Methods: Here we investigated the expression of NF-kappa B and the main UPR markers X-box binding protein 1 (XBP1), basic leucine-zipper transcription factor 6 (ATF6) and phosphorylated eukaryotic initiation factor-2 alpha (p-elF2) in mutated SOD1(G93A) cell models of ALS, as well as their modulation by lipopolysaccharide and ER-stressing (tunicamycin) stimuli. Results: Expression of NF-kappa B was enhanced in the presence of SOD1G93A. Lipopolysaccharide did not induce the UPR in NSC34 cells and motor neurons in a mixed motor neuron-glia coculture system. The induction of the UPR by tunicamycin was accompanied by activation of NF-kappa B in NSC34 cells and motor neurons. Conclusion: Our data linked two important pathogenic mechanisms of ALS, ER stress and NF-kappa B signalling, in motor neurons. (C) 2014 Elsevier B.V. All rights reserved.