The role of s-nitrosylation and s-glutathionylation of protein disulphide isomerase in protein misfolding and neurodegeneration

Abstract

Neurodegenerative diseases involve the progressive loss of neurons, and a pathological hallmark is the presence of abnormal inclusions containing misfolded proteins. Although the precise molecular mechanisms triggering neurodegeneration remain unclear, endoplasmic reticulum (ER) stress, elevated oxidative and nitrosative stress, and protein misfolding are important features in pathogenesis. Protein disulphide isomerase (PDI) is the prototype of a family of molecular chaperones and foldases upregulated during ER stress that are increasingly implicated in neurodegenerative diseases. PDI catalyzes the rearrangement and formation of disulphide bonds, thus facilitating protein folding, and in neurodegeneration may act to ameliorate the burden of protein misfolding. However, an aberrant posttranslational modification of PDI, S-nitrosylation, inhibits its protective function in these conditions. S-nitrosylation is a redox-mediated modification that regulates protein function by covalent addition of nitric oxide- (NO-) containing groups to cysteine residues. Here, we discuss the evidence for abnormal S-nitrosylation of PDI (SNO-PDI) in neurodegeneration and how this may be linked to another aberrant modification of PDI, S-glutathionylation. Understanding the role of aberrant S-nitrosylation/S-glutathionylation of PDI in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions in the future.

Figure 1

Domains of PDIA1. TRX-like domains representing catalytic active domains a a′. The b domain and b′ are catalytically inactive. The linker region is responsible for binding to the substrate. The C terminal is followed by an ER retrieval signal KDEL.

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.

Figure 3

S-glutathionylation of PDI. Nitrosative stress from an exogenous agent (PABA/NO) increases intracellular NO and leads to the production of SNO-PDI. However, this may result in a decrease in GSSG/GSH ratio and increases in the free cellular pool of GSH. GSH then binds to the catalytic (a, a′) domains of PDI, resulting in S-glutathionylation (P-SSG) of its cysteine residues and attenuation of its protective isomerase and chaperone activity.