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The endoplasmic reticulum (ER) is a subcellular compartment playing a central role in calcium storrage and calcium signalling. Furthermore, all newly synthesized membrane and secretory proteins are folded and processed in this subcellular compartment. These are strictly calcium-dependent processes that need for correct functioning a calcium activity in the range close to that of the extracellular space. Under conditions associated with ER dysfunction, unfolded proteins accumulate in the lumen of the ER. This is the warning signal for activation of highly conserved stress responses, including the unfolded protein response (UPR), necessary to restore normal functioning of the ER, and the ER-associated degradation (ERAD) to degrade unfolded proteins at the proteasome. In acute pathological states of the brain, such as stroke, neurotrauma, epileptic seizures, and in degenerative diseases ER functioning is impaired in multiple ways. These include disturbances of ER calcium homeostasis, impairment of ERAD and UPR, and insufficient proteasome functioning which triggers secondary ER dysfunction. Therapeutic interventions designed to suppress the pathological process culminating in neuronal cell death in acute and degenerative diseases of the brain could therefore focus on strategies aimed at improving the capability of neurons to withstand conditions associated with ER dysfunction |
