ER and Oxidative Stress: Implications in Disease

Publisher Summary The endoplasmic reticulum (ER) is a membranous network extending throughout the cytoplasm of the eukaryotic cell and is contiguous with the nuclear envelope. The ER is the site of synthesis of sterols, lipids, core-asparagine linked oligosaccharides, and membrane and secreted proteins biosynthesis. It has evolved as a protein folding machine and a major intracellular signaling organelle and provides a unique environment for protein folding, assembly, and disulfide bond formation prior to transit to the Golgi compartment. The unfolded protein response (UPR) evolved as a complex homeostatic mechanism to balance the load of newly synthesized proteins with the capacity for chaperone assisted protein folding in the lumen of the ER. UPR plays an important role in numerous disease states, including diabetes mellitus, atherosclerosis, neoplasia, and neurodegenerative diseases. The development of Type 2 diabetes is associated with a combination of insulin resistance in fat, muscle, and liver and a failure of pancreatic beta cells to adequately compensate by increased insulin production. There is also evidence that oxidative damage is associated with development of the diabetic state. Antioxidants have been reported to preserve glucose stimulated insulin secretion, prevent apoptosis, and expand beta cell mass, without significantly affecting cell proliferation. Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, represent a large class of conformational diseases associated with accumulation of abnormal protein aggregates in and around affected neurons. Oxidative stress and protein misfolding play critical roles in the pathogenesis of these neurodegenerative diseases.