Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Abstract

A B S T R A C TThe 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. ß

Protective HSP70 Induction by Z-Ligustilide against Oxygen–Glucose Deprivation Injury <i>via</i> Activation of the MAPK Pathway but Not of HSF1

“…36) Brain ischemia also damages protein degradation pathways, causing the accumulation of ubiquitinated proteins. 37) In this study, we also discovered that Z-ligustilide reduced the accumulation of ubiquitinated proteins induced by both MG132 and OGD-Reoxy and provided the evidence that blocking protein aggregation may be an important mechanism for the protection of Z-ligustilide against OGD-Reoxy induced injury. Importantly, HSP70 induction played a key role during this process.…”

A molecular signature for delayed graft function

“…The third transcript, BTN3A2, originates from the gene located in the juxta‐telomeric region of the HLA locus and is involved in the adaptive immune response and inhibition of INFγ release. GABBR1 has been associated with proteasome activation and cytoskeleton remodelling, with differential responses to IRI, dependent upon severity of insult (Caldeira, Salazar, Curcio, Canzoniero, & Duarte, 2014). UBD has also previously been implicated in renal pathology, via involvement in inflammatory‐mediated signalling and immune system modulation.…”

rAAV8-733-Mediated Gene Transfer of CHIP/Stub-1 Prevents Hippocampal Neuronal Death in Experimental Brain Ischemia

“…25 Results of experiments in both in vivo and in vitro models of brain ischemia have disclosed an increased level of clustered ubiquitinated proteins that may lead to protein aggregates in neurons of the hippocampal CA1 region and ensuing cell death. 10 It has been suggested that irreversible aggregation of translational complex components, chaperones, and protein folding enzymes following brain ischemia lead to inhibition of translation and subsequent neuron death. 26 Consistent with this view, we detected augmented levels of ubiquitinated proteins after either OGD followed by 24 hr of reperfusion or GBI followed by 3 hr of reperfusion, particularly among high molecular weight protein bands in western blots.…”

“…10 Following OGD, ubiquitin content was significantly increased in the hippocampal slices (p = 0.0046), while a trend toward increased ubiquitination in tissue transduced with GFP was not statistically significant (p = 0.0722) ( Figure 5). However, the level of ubiquitinated protein in CHIP-transduced slices was comparable to controls (p = 0.9885).…”

“…8 However, activation of AKT by oxidative stress may facilitate cell death depending on context, 9 indicating that dynamic phosphorylation of AKT may affect several mechanisms related to cell fate. Proteostasis defects after brain ischemia are well documented, including disruption of the ubiquitin-proteasome system (UPS), 10 endoplasmic reticulum (ER) stress, 11,12 and inhibition of global protein synthesis mediated by the phosphorylation of eukaryotic initiation factor-2a (eIF2a) at serine 51 (Ser51). 13 These findings suggest that modulation of key components related to integrity of the proteome may promote neuroprotection after an ischemic insult.…”