The Role of S-Nitrosylation and S-Glutathionylation of Protein Disulphide Isomerase in Protein Misfolding and Neurodegeneration

Figure 2

Cell surface PDI, NO, and SNO-PDI. (A) Cell surface PDI reduces NO from extracellular SNO proteins (SNO-P) and in the process undergoes thiol modification. (B) Hyperactivation of the NMDAr leads to an intracellular influx of Ca²⁺ ions (NMDAr may also undergo reversible S-nitrosylation to ameliorate excessive activity). (C) Inhibition of mitochondria contributes to an increase in intracellular NO which is potentially oxidized by O₂ leading to an increase in NO, nNOS, ROS, and RNS. (D) Increases in RNS/ROS alters the ER redox environment, and NO S-nitrosylates Ca²⁺ ryanodine (Ryn) receptor leading to a disruption in Ca²⁺ homeostasis. (E) ER-resident proteins such as PDI are vulnerable to S-nitrosylation, deactivating its isomerase and chaperone activity, leading to accumulation of misfolded proteins, ER stress, and UPR induction.