Abstract:
Abnormalities in endoplasmic reticulum (ER) homeostasis cause ER stress which initiates unfolded protein response (UPR). Aberrant protein S-nitrosylation and failure in UPR activation has shown be underlying causes of neurodegeneration, however exact molecular and cellular mechanism still remain elusive. Therefore, the present study elucidates the relationship between the unfolded protein response (UPR) during ER stress and aberrant S-nitrosylation levels that ultimately results in neuronal toxicity leading to neurodegeneration.
The experimental animals, Balb/c mice were divided into 2 groups (n=8, each). Dithiothreitol (DTT) was used to induce UPR following ER stress. An optimum dose of DTT (75 mg/kg) was administered after every 24hr for three consecutive days. Histological and immunohistochemical examination showed clear signs of neurodegeneration and increased S-nitrosocystine antibody reactivity in cortex and hippocampal sections of mice brain respectively, along with atrophied neuronal morphology, following DDT exposure. Data of differentially expressed proteins during ER stress from ESI-QTOFMS/MS was used to perform in silico analysis to predict the plausible S-nitrosylation sites in proteomic data set. Many plausible S-nitrocystine sites were predicted via Group-based Prediction System-S-nitrosothiols (GPS-SNO 1.0.) while protein-protein interactions of proteomic data set showed interactions with some important proteins involved in signaling cascades associated with neurodegeneration.
In conclusion, the findings of the present work may contribute to the existing pool of knowledge and provide a better understanding of complex molecular association of aberrant S-nitrosylation of proteins in neurodegeneration. This may help in further elucidation of plausible aberrant molecular/signaling pathways during ER stress which may lead to neurodegeneration
