P4HB and amyotrophic lateral sclerosis: However, S-nitrosation of PDI Cys residues in its two thioredoxin-like domains inactivates both its chaperone and isomerase activities, which leads to the accumulation of misfolded proteins, in particular ALS-associated proteins like SOD1, and to a persistent ER stress that ultimately triggers neuronal injury and death (Uehara et al., 2006; Walker et al., 2009; Chen et al., 2012, 2013; Jeon et al., 2014; Medinas et al., 2018; Matsusaki et al., 2020).