Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?
Autor(a) principal: | |
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Data de Publicação: | 2014 |
Outros Autores: | , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/25489 https://doi.org/10.1016/j.pneurobio.2013.10.003 |
Resumo: | 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 ubiquitincontaining 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. |
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Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?Ubiquitin–proteasome systemBrain ischemiaExcitotoxicityProteasome inhibitorsThe 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 ubiquitincontaining 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.The work in the authors laboratory is funded by Fundação para a Ciencia e Tecnologia, COMPETE (Programa Operacional Factores de Competitividade), QREN and FEDER (Fundo Europeu de Desenvolvimento Regional) (PTDC/SAU-NMC/120144/2010, PTDC/NEUNMC/ 0198/2012 and PEst-C/SAU/LA0001/2011).Elsevier Ltd.2014info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/25489http://hdl.handle.net/10316/25489https://doi.org/10.1016/j.pneurobio.2013.10.003enghttp://www.sciencedirect.com/science/article/pii/S0301008213001032#Caldeira, Margarida V.Salazar, Ivan L.Cursio, MicheleCanzoniero, Lorella M. T.Duarte, Carlos B.info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2020-05-29T09:42:06Zoai:estudogeral.uc.pt:10316/25489Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:56:01.023661Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe? |
title |
Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe? |
spellingShingle |
Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe? Caldeira, Margarida V. Ubiquitin–proteasome system Brain ischemia Excitotoxicity Proteasome inhibitors |
title_short |
Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe? |
title_full |
Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe? |
title_fullStr |
Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe? |
title_full_unstemmed |
Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe? |
title_sort |
Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe? |
author |
Caldeira, Margarida V. |
author_facet |
Caldeira, Margarida V. Salazar, Ivan L. Cursio, Michele Canzoniero, Lorella M. T. Duarte, Carlos B. |
author_role |
author |
author2 |
Salazar, Ivan L. Cursio, Michele Canzoniero, Lorella M. T. Duarte, Carlos B. |
author2_role |
author author author author |
dc.contributor.author.fl_str_mv |
Caldeira, Margarida V. Salazar, Ivan L. Cursio, Michele Canzoniero, Lorella M. T. Duarte, Carlos B. |
dc.subject.por.fl_str_mv |
Ubiquitin–proteasome system Brain ischemia Excitotoxicity Proteasome inhibitors |
topic |
Ubiquitin–proteasome system Brain ischemia Excitotoxicity Proteasome inhibitors |
description |
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 ubiquitincontaining 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. |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/25489 http://hdl.handle.net/10316/25489 https://doi.org/10.1016/j.pneurobio.2013.10.003 |
url |
http://hdl.handle.net/10316/25489 https://doi.org/10.1016/j.pneurobio.2013.10.003 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
http://www.sciencedirect.com/science/article/pii/S0301008213001032# |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Elsevier Ltd. |
publisher.none.fl_str_mv |
Elsevier Ltd. |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
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1799133845529821184 |