Nuclear SOD1 links ATM-CHK2 signaling to ADH5/GSNOR transcription in SHSY-5Y SOD1G93A cellular models of ALS.

The activity of S-nitrosoglutathione reductase (ADH5/GSNOR) has been proposed being essential to limit oxidative stress and preserve mitochondrial quality control. Here we identify a redox-dependent ATM-CHK2-SOD1 signaling axis that drives ADH5/GSNOR transcription in SH-SY5Y cells expressing the ALS-associated SOD1G93A mutant. ATM-CHK2 activation promotes the interaction of SOD1 with CHK2, leading to SOD1 nuclear translocation and binding to the ADH5 promoter. Pharmacological inhibition of ATM or CHK2 abolishes these effects. ADH5/GSNOR overexpression protects cells from SOD1G93A-induced toxicity suggesting that the modulation of GSNOR activity may represent a potential strategy to restore redox homeostasis in ALS.