Changes in neuronal @entity460 activity in the various subcellular compartments have divergent effects on affected cells. In the cytoplasm and mitochondria, where @entity460 activity is normally low, a prolonged excessive rise in free @entity460 levels is believed to be toxic, in the endoplasmic reticulum (ER), in contrast, @entity460 activity is relatively high and severe stress is caused by a depletion of ER @entity460 stores. Besides its role in cellular @entity460 signaling, the ER is the site where membrane and secretory proteins are folded and processed. These @entity460 -dependent processes are fundamental to normal cell functioning. Under conditions of @entity409 unfolded proteins accumulate in the ER lumen, a signal responsible for activation of the unfolded protein response (UPR) and the ER-associated degradation (ERAD). UPR is characterized by activation of two ER-resident kinases, @entity7952 ( @entity7952 ) and @entity5593 . @entity7952 induces phosphorylation of the eukaryotic initiation factor ( @entity12465 ), resulting in a shut-down of translation at the initiation step. This stress response is needed to block new synthesis of proteins that cannot be correctly folded, and thus to protect cells from the effect of unfolded proteins which tend to form toxic aggregates. @entity5593 , on the other hand, is turned after activation into an endonuclease that cuts out a sequence of 26 bases from the coding region of @entity5594 mRNA. Processed @entity5594 mRNA is translated into the respective protein, an active transcription factor specific for ER stress genes such as @entity1477 . In @entity697 and @entity179 , the ER @entity460 pool is a primary target of toxic metabolites or intermediates, such as @entity26 free radicals, produced during the pathological process. Affected neurons need to activate the entire UPR to cope with the severe form of stress induced by @entity409 . This stress response is however hindered under conditions where protein synthesis is suppressed to such an extent that processed @entity5594 mRNA is not translated into the processed @entity5594 protein ( @entity3790 ). Furthermore, activation of ERAD is important for the degradation of unfolded proteins through the ubiquitin/proteasomal pathway, which is impaired in @entity697 and @entity179 , resulting in further ER stress. ER functioning is thus impaired in two different ways: first by the direct action of toxic intermediates, produced in the course of the pathological process, hindering vital ER reactions, and second by the inability of cells to fully activate UPR and ERAD, leaving them unable to withstand the severe form of stress induced by @entity409 .

Endoplasmic reticulum: a primary target in various XXXX and degenerative diseases of the brain.

@entity697 :: ('MESH:D000208', 'Disease') :: ['acute disorders'] @entity1477 :: ('3309', 'Gene') :: ['grp78'] @entity12465 :: ('83939', 'Gene') :: ['eIF2alpha'] @entity26 :: ('MESH:D010100', 'Chemical') :: ['oxygen'] @entity409 :: ('MESH:D008107', 'Disease') :: ['ER dysfunction'] @entity5594 :: ('7494', 'Gene') :: ['XBP1', 'xbp1'] @entity7952 :: ('9451', 'Gene') :: ['PKR-like ER kinase', 'PERK'] @entity3790 :: ('5624', 'Gene') :: ['XBP1(proc)'] @entity179 :: ('MESH:D019636', 'Disease') :: ['degenerative diseases'] @entity460 :: ('MESH:D002118', 'Chemical') :: ['calcium'] @entity5593 :: ('2081', 'Gene') :: ['IRE1']
@entity697 :: (MESH:D000208,Disease) :: ['acute disorders']
