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.

Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome

“…ROS and NO can both react with thiol groups in proteins potentially corrupting their structure and function. Initially, Snitrosylation of target thiol groups can provide such proteins with at least limited protection against irreversible oxidative damage under pathological levels of oxidative and nitrosative stress (O&NS) [18,28]. In contrast, irreversible oxidation of such thiols can impede the normal physiologic modification by S-nitrosylation, thereby interfering with normal cellular signaling [4,35].…”

“…It is worthy of note that S-nitrosylation facilitates additional oxidation reactions with environmental ROS, leading to the formation of sulfonic, sulfenic, and sulfinic acid derivatives [18,104]. Sulfonation responses are held to be functionally irreversible, despite the recent discovery of reducing enzymes [2], leading to irrevocable pathological alterations in protein structure and activity [19,105].…”

“…Under normal physiological conditions, this posttranslational modification acts as a signaling mechanism regulating cellular protein-protein interactions [11,17], protein activity [18,19], and protein localization within cells [20,21]. Hundreds of proteins are identified which have possible S-nitrosylation sites [22].…”

The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders

“…Excessive levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to O&NS damage to proteins and DNA and lipid peroxidation and the subsequent production of reactive aldehydes and ketones [5,13]. This has a number of potentially serious pathological consequences.…”

“…These and other mechanisms explain why chronic O&NS and chronic inflammation co-exist and self-amplify in a vicious self-sustaining spiral [6,18]. Excessive levels of RNS and ROS also exert pathological effects by adversely affecting the posttranslational modification of proteins, leading to the disruption of cellular redox signalling [13].…”