Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6286525 | Progress in Neurobiology | 2014 | 20 Pages |
Abstract
The ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitin-containing proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review.
Keywords
PRUMCAOAPVcdk5NMDAReIF2α3-MAGKAPGRP78TRPMATF4HECTDUBα-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acidNedd4UBAPI3 KUCHBCOubiquitin associated domainPSD-95PDIPSDERADtPANOSeNOSUblAMPAAMPAROGDN-methyl-d-aspartateNMDA15-deoxy-Δ12,14-Prostaglandin J23-methyladenineAPC/CMdm2PKR-like ER kinase[Ca2+]ianaphase-promoting complex/cyclosomeDeubiquitinating enzymesendothelial NOSmiddle cerebral artery occlusionER-Associated DegradationPost-synaptic densityCHOPRingUbiquitin-like domainregulatory particleBlood–brain barrierBBBcyclin-dependent kinase-5endoplasmic reticulumeukaryotic initiation factor 2αintracellular Ca2+ concentrationphosphoinositide 3-kinaseactivating transcription factor 4tissue plasminogen activatorMarksOxygen and glucose deprivationtransient receptor potential melastatinnitric oxide synthaseHerpglucose-regulated protein 78Protein disulphide isomeraseguanylate kinase-associated proteinPERKreally interesting new geneKainateNMDA receptorsAMPA receptors
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Authors
Margarida V. Caldeira, Ivan L. Salazar, Michele Curcio, Lorella M.T. Canzoniero, Carlos B. Duarte,