Endoplasmic Reticulum Dysfunction in Brain Pathology: Critical Role of Protein Synthesis

Author(s): Wulf Paschen

Journal Name: Current Neurovascular Research

Volume 1 , Issue 2 , 2004

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The endoplasmic reticulum (ER) is a subcellular compartment playing a central role in folding and processing membrane and secretory proteins. The importance of these reactions for normal cellular function is indicated by the fact that blocking of these processes is potentially lethal for cells. Under conditions associated with ER dysfunction, unfolded proteins accumulate in the ER lumen. This is the warning signal of two stress responses: the unfolded protein response (UPR) required for inducing the new synthesis of chaperons to refold the unfolded proteins, and the ER-associated degradation (ERAD) to degrade unfolded proteins at the proteasome. Cells in which UPR and ERAD cannot be activated to such an extent that ER function is restored die by apoptosis. In acute pathological states of the brain, including stroke, neurotrauma and epileptic seizures, and in degenerative diseases ER function is impaired in multiple ways. These include oxidative stress, nitric oxide-induced inactivation of the ER calcium pump resulting in disturbances of ER calcium homeostasis and impairment of UPR and ERAD. Furthermore, proteasomal function is impaired which causes secondary ER dysfunction. The only way to escape this potentially lethal cycle is to induce UPR and thus to activate new synthesis of ER chaperon GRP78 to levels sufficient to refold unfolded proteins. ER dysfunction may induce a state of tolerance, impair cellular functions, or induce apoptosis, depending on the severity and duration and the cell type affected. This review focuses on the possible role of ER dysfunction in the pathological process induced by transient cerebral ischemia.

Keywords: endoplasmic reticulum associated degradation, glucose regulated protein, nitric oxide, unfolded protein response

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Article Details

Year: 2004
Page: [173 - 181]
Pages: 9
DOI: 10.2174/1567202043480125
Price: $65

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