title: Role of the ubiquitin-proteasome system in brain ischemia: friend or foe?
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.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Margarida V
authors.initials: MV
authors.lastname: Caldeira
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal; Doctoral Programme in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Institute for Interdisciplinary Research, University of Coimbra (IIIUC), Portugal.
authors.forename: Ivan L
authors.initials: IL
authors.lastname: Salazar
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal; Department of Science and Technology, University of Sannio, Benevento, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Curcio
authors.affiliation: Department of Science and Technology, University of Sannio, Benevento, Italy.
authors.forename: Lorella M T
authors.initials: LM
authors.lastname: Canzoniero
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal; Department of Life Sciences, University of Coimbra, 3004-517 Coimbra, Portugal. Electronic address: cbduarte@ci.uc.pt.
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Duarte
mesh_terms: D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D057149:Ubiquitinated Proteins / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D057149:Ubiquitinated Proteins; D046988:Proteasome Endopeptidase Complex
keywords: 15-deoxy-Δ(12,14)-prostaglandin J2; 15d-PHJ(2); 3-MA; 3-methyladenine; AMPA; AMPA receptors; AMPAR; APC/C; APV; ATF(4); BBB; BCO; Brain ischemia; C/EBP homologues protein; CHOP; CP; Cdk5; D-aminophosphonovalerate; DUB; E6-AP carboxyl terminus; ER; ER-associated degradation; ERAD; Excitotoxicity; GKAP; GRP78; HECT; HERP; KA; MARKS; MCAO; Mdm2; Mib2; Mind Bomb-2; N-methyl-d-aspartate; NCX3; NMDA; NMDA receptors; NMDAR; NOS; Nedd4; OGD; PDI; PERK; PI3 K; PKR-like ER kinase; PSD; PSD-95; Proteasome inhibitors; Pru; RING; RP; TRPM; UBA; UBL; UCH; UIM; UPR; UPS; USP; Ubiquitin–proteasome system; VGLUT; X-box binding protein 1; XBP1; [Ca(2+)](i); activating transcription factor 4; anaphase-promoting complex/cyclosome; ataxic mouse; ax(J); bilateral carotid occlusion; blood–brain barrier; catalytic particle; cyclin-dependent kinase-5; deubiquitinating enzymes; eIF2α; eNOS; endoplasmic reticulum; endothelial NOS; eukaryotic initiation factor 2α; glucose-regulated protein 78; guanylate kinase-associated protein; homocysteine-inducible, ER-stress inducible protein; intracellular Ca(2+) concentration; kainate; mESPC; middle cerebral artery occlusion; mini excitatory post-synaptic current; murine-double minute 2; myristoylated, alanine-rich C-kinase substrate; neuronal-precursor cell-expressed developmentally downregulated gene 4; nitric oxide synthase; oxygen and glucose deprivation; phosphoinositide 3-kinase; pleckstrin-like receptor for ubiquitin; post-synaptic density; post-synaptic density associated protein 95; protein disulphide isomerase; really interesting new gene; regulatory particle; sodium–calcium exchanger type-3; tPA; tissue plasminogen activator; transient receptor potential melastatin; ubiquitin C-terminal hydrolases; ubiquitin associated domain; ubiquitin specific protease; ubiquitin-interacting motif; ubiquitin-like domain; ubiquitin–proteasome system; unfolded protein response; vesicular glutamate transporters; α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid