P4HB and amyotrophic lateral sclerosis: Increased PDI expression has been reported in neurodegenerative diseases, to ease ER stress from the accumulation of misfolded proteins, however, the neuroprotective effect of its disulfide-isomerase and chaperone activity can be inhibited by S-nitrosylation (Uehara et al., 2006; Andreu et al., 2012), discussed below with respect to AD, PD, and ALS (summarized in Figure 2).