Protein disulfide isomerases in neurodegeneration: From disease mechanisms to biomedical applications

Abstract

a b s t r a c tProtein disulfide isomerases (PDIs) are a family of foldases and chaperones primarily located at the endoplasmic reticulum that catalyze the formation and isomerization of disulfide bonds thereby facilitating protein folding. PDIs also perform important physiological functions in protein quality control, cell death, and cell signaling. Protein misfolding is involved in the etiology of the most common neurodegenerative diseases, including Alzheimer, Parkinson, amyotrophic lateral sclerosis, Prion-related disorders, among others. Accumulating evidence indicate altered expression of PDIs as a prominent and common feature of these neurodegenerative conditions. Here we overview most recent advances in our understanding of the possible functional contribution of PDIs to neurodegeneration, depicting a complex and poorly understood scenario. Possible therapeutic benefits of targeting PDIs in a disease context and their use as biomarkers are discussed.

New Insights onNOXEnzymes in the Central Nervous System

“…PDI is an oxidoreductase that is involved in oxidative protein folding in the endoplasmic reticulum with an emerging role in aggregation neurodegenerative diseases (5).…”

Protein Disulfide Isomerase: Structure, Mechanism of Oxidative Protein Folding and Multiple Functional Roles

“…It is a major ER protein that functions as a molecular chaperone and a folding enzyme by catalyzing the formation, cleavage, and rearrangement of the disulfide bonds in unfolded or misfolded proteins [3][4][5] . Recent studies have convincingly demonstrated that PDI indeed plays important roles in both the physiology and pathophysiology of disease states including diabetes [29] , cardiovascular diseases [30] , cancer [32] , neurodegenerative conditions [33] and the entry of pathogens in infectious diseases [34] . However, the precise roles for PDI in these diseases states have not yet been established.…”

“…Recent studies have convincingly shown that PDI plays important roles in the physiology as well as pathophysiology of the disease states including diabetes [28] , cardiovascular diseases [66] , cancer [67] neurodegenerative conditions [68] and the entry of pathogens in infectious diseases [69] . However, the precise roles for PDI in each of these diseases have not yet been elucidated.…”

“…Quercetin-3-rutinoside, a flavonol highly abundant in common foods, inhibits PDI and blocks thrombus formation both in vitro and in vivo [31] . It also plays important roles in cancer [32] , neurodegenerative conditions [33] and mediates entry of pathogens in infectious diseases [34] . Keeping the above views in mind, in this review we have discussed PDI structure, catalysis of disulfide bond formation and isomerization and its role as chaperone and in pathophysiology [35] .…”

The redox switch that regulates molecular chaperones

“…PDI has been shown to accumulate with neurofibrillary tangles and the dystrophic neurites of senile plaques in AD brain, and with FUS-positive ubiquitinated inclusions in human ALS patient spinal cords (107,108). Not only was there an increase in PDI expression in AD, PD, and ALS brain, the amount of S-nitrosylated PDI was also substantial (107,(109)(110)(111)(112)(113)(114)(115). S-nitrosylation of PDI, through the redox-active thiols of the a and a' domains, inhibits enzyme activity.…”