Autor(es):
Caldeira, Margarida V. 
; Salazar, Ivan L. ; Cursio, Michele ; Canzoniero, Lorella M. T. ; Duarte, Carlos B.
Data: 2014
Identificador Persistente: http://hdl.handle.net/10316/25489
Origem: Estudo Geral - Universidade de Coimbra
Assunto(s): Ubiquitin–proteasome system; Brain ischemia; Excitotoxicity; Proteasome inhibitors
Descrição
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. 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).
