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

•Endoplasmic reticulum stress is involved in the pathogenesis of amyotrophic lateral sclerosis.•NF-κB is activated in mutated SOD1G93A motor neurons.•LPS does not induce endoplasmic reticulum stress in motor neurons.•The induction of endoplasmic reticulum stress is accompanied by activation of NF-κB in motor neurons.•Our data link unfolded protein response and the NF-κB pathway in motor neurons.

BackgroundRecent 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-κB pathway.MethodsHere we investigated the expression of NF-κB and the main UPR markers X-box binding protein 1 (XBP1), basic leucine-zipper transcription factor 6 (ATF6) and phosphorylated eukaryotic initiation factor-2α (p-eIF2) in mutated SOD1G93A cell models of ALS, as well as their modulation by lipopolysaccharide and ER-stressing (tunicamycin) stimuli.ResultsExpression of NF-κB 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-κB in NSC34 cells and motor neurons.ConclusionOur data linked two important pathogenic mechanisms of ALS, ER stress and NF-κB signalling, in motor neurons.