Possible role of protein disulfide isomerases (PDIs) in ALS. PDIs are up-regulated in diverse models of ALS in addition to tissue from patients. They also have been suggested as possible biomarkers to monitor disease progression using body fluids. PDIA1, in the figure PDI, colocalized with protein inclusions containing FUS, TDP43 or SOD1 in human tissue and mouse models of ALS. The exact contribution of PDIs to ALS is currently a matter of debate. PDIs could have a protective role through decreasing protein aggregation and global ER stress. S-nitrosylation appears to inactivate PDI and contribute to ER stress. Reactive oxygen species (ROS) produced from redox folding (disulfide bond formation) may also contribute to the generation of protein aggregates.
