PDI, Reactive oxygen species stress and Polyphenolic Phytochemicals: Implications for Neurodegenerative Diseases

PDI, protein disulfide isomerase, is one of the most versatile proteins and highly expressed in mammalian cells because there is a vast number of proteins that must undergo processing before secretion to their final destinations. PDI has several functions: oxidation of nascent proteins and isomerization of existing disulfide bonds. It also possesses chaperone activity and participates in protein degradation. Because of its structure, PDI can exist in a reduced or oxidized form. In mammalian cells it is mostly reduced due to the high demand of disulfide bond shuffling of secreted proteins within the ER, PDI a, a\u27, and b\u27 posses the ability to facilitate substrate folding. In our experiments we are using rat PDI and according to the sequence there are cysteine residues located in a and a\u27 domains. These cysteine residues may contribute to the catalytic activity of this domain and will be analyzed in future studies. Misfolded proteins, and the associated endoplasmic reticulum (ER) stress, are emerging as hallmarks of age- and neurodegeneration-related disorders such as Huntington\u27s disease (HD), Alzheimer\u27s disease (AD), Parkinson\u27s disease (PD) and amyotrophic lateral sclerosis. Recent and compelling evidence has linked nitrosative stress and the ER-resident oxidoreductase, protein disulfide isomerase (PDI), to the pathogenesis of PD and AD. Overexpression of PDI has been found to reduce the formation of polyubiquitinated proteins, making the oxidoreductase an important target for therapeutic intervention in PD, AD and other age- and neurodegeneration-related disorders. We demonstrate the NO-scavenging ability of the biphenolic natural products curcumin and masoprocol and the concomitant prevention of S-nitrosylation of PDI by a model NO-donor. Furthermore, both ethnopharmaceuticals accelerate protein fold acquisition in their neat and nitrated forms, making them attractive candidates for prevention of age- and neurodegeneration-related diseases