Endoplasmic Reticulum Stress Inhibition Protects against Excitotoxic Neuronal Injury in the Rat Brain

Sokka, Anna-Leena; Putkonen, Noora; Mudò, Giuseppa; Pryazhnikov, Evgeny; Reijonen, Sami; Khiroug, Leonard; Belluardo, Natale; Lindholm, Dan; Korhonen, Laura

doi:10.1523/jneurosci.4289-06.2007

Cited by 292 publications

(280 citation statements)

References 45 publications

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“…Salubrinal treatment. Mice received daily intraperitoneal injections of 1 mg kg 21 of salubrinal (Calbiochem), or vehicle (diluted DMSO in saline (Sigma)) 25 , for 7 days from 8 w.p.i. Experimental analyses.…”

Section: Methodsmentioning

confidence: 99%

“…Salubrinal penetrates the blood-brain barrier ( Supplementary Fig. 8) and has been used for modulation of eIF2a-P-dependent effects in endoplasmic reticulum stressmediated processes in the central nervous system in vivo after peripheral administration [25][26][27] . Mice were inoculated with prions and received hippocampal injections of lentiviruses expressing GADD34 (LV-GADD34), anti-PrP shRNA (LV-shPrP) or yellow fluorescent protein (YFP) only (LV-control) at 5 w.p.i., allowing 4 weeks for lentiviral expression to occur, before testing the effects of treatment on eIF2a-P levels and neurotoxicity at 9 w.p.i.…”

Section: Research Lettermentioning

confidence: 99%

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Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Moreno

Radford

Peretti

et al. 2012

Nature

551

617

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The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the a-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2a-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases 1-4 , but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2a-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2a-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2a-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2a-P dephosphorylation 5 , increased eIF2a-P levels, exacerbating neurotoxicity and significantly reducing survival in priondiseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.Neurodegenerative diseases pose an ever-increasing challenge for society and health care systems worldwide, but their molecular pathogenesis is still largely unknown and no curative treatments exist. Alzheimer's (AD), Parkinson's (PD) and prion diseases are separate clinical and pathological conditions, but it is likely they share common mechanisms leading to neuronal death. Mice with prion disease show misfolded prion protein (PrP) accumulation and develop extensive neurodegeneration (with profound neurological deficits), in contrast to mouse models of AD or PD, in which neuronal loss is rare. Uniquely therefore, prion-infected mice allow access to mechanisms linking protein misfolding with neuronal death. Prion replication involves the conversion of cellular PrP, PrP C , to its misfolded, aggregating conformer, PrP Sc , a process leading ultimately to neurodegeneration 6 . We have previously shown rescue of neuronal loss and reversal of early cognitive and morphological changes in prion-infected mice by depleting PrP in neurons, preventing prion replication and ab...

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Section: Methodsmentioning

confidence: 99%

Section: Research Lettermentioning

confidence: 99%

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Moreno

Radford

Peretti

et al. 2012

Nature

551

617

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“…SAL is the most commonly used ER stress inhibitor, and it acts by selectively inhibiting eIF2α dephosphorylation both in vitro and in vivo [33,37] . In this study, we first examined the expression of phosphorylated eIF2α in the cortex at 6 h, 12 h www.chinaphar.com Gao B et al Acta Pharmacologica Sinica npg and 24 h after ischemic preconditioning.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that SAL does not affect the UPR targets Xbp-1, GRP78, and GRP94 in PC12 cells treated for 36 h [33] . However, some studies have also reported that SAL could reduce the increase in GRP78 expression induced by α-TEA (RRR-α-tocopherol ether-linked acetic acid analog) or KA (kainic acid) [37,38] . This discrepancy is partly because previous research only examined the effects of SAL on normal cells.…”

Section: Discussionmentioning

confidence: 99%

The endoplasmic reticulum stress inhibitor salubrinal inhibits the activation of autophagy and neuroprotection induced by brain ischemic preconditioning

et al. 2013

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Aim: To investigate whether endoplasmic reticulum (ER) stress participates in the neuroprotective effects of ischemic preconditioning (IPC)-induced neuroprotection and autophagy activation in rat brains. Methods: The right middle cerebral artery in SD rats was occluded for 10 min to induce focal cerebral IPC, and was occluded permanently 24 h later to induce permanent focal ischemia (PFI). ER stress inhibitor salubrinal (SAL) was injected via intracerebral ventricle infusion 10 min before the onset of IPC. Infarct volume and motor behavior deficits were examined after the ischemic insult. The protein levels of LC3, p62, HSP70, glucose-regulated protein 78 (GRP 78), p-eIF2α and caspase-12 in the ipsilateral cortex were analyzed using immunoblotting. LC3 expression pattern in the sections of ipsilateral cortex was observed with immunofluorescence. Results: Pretreatment with SAL (150 pmol) abolished the neuroprotective effects of IPC, as evidenced by the significant increases in mortality, infarct volume and motor deficits after PFI. At the molecular levels, pretreatment with SAL (150 pmol) significantly increased p-eIF2α level, and decreased GRP78 level after PFI, suggesting that SAL effectively inhibited ER stress in the cortex. Furthermore, the pretreatment with SAL blocked the IPC-induced upregulation of LC3-II and downregulation of p62 in the cortex, thus inhibiting the activation of autophagy. Moreover,SAL blocked the upregulation of HSP70, but significantly increased the cleaved caspase-12 level, thus promoting ER stress-dependent apoptotic signaling in the cortex. Conclusion: ER stress-induced autophagy might contribute to the neuroprotective effect of brain ischemic preconditioning.

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“…Prolonged eIF2α inactivation induces the protein phosphatase regulatory subunit GADD34, which reverses eIF2α-mediated translational inhibition promoting programmed cell death (Brush et al, 2003). As such, phosphatase inhibitors like salubrinal that prolong translational arrest are protective against ER-stress ( Boyce et al, 2005;Sokka et al, 2007). And while activation of CHOP-10 may enhance mitochondrial function through the direct regulation of heat shock proteins including mtDnaJ and ClpP, deletion of CHOP-10 is neuroprotective after stroke (Tajiri et al, 2004;Zhao et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

Halterman

Jesus

Rempe

et al. 2008

Molecular and Cellular Neuroscience

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Understanding the mechanisms governing the switch between hypoxia-induced adaptive and pathological transcription may reveal novel therapeutic targets for stroke. Using an in vitro hypoxia model that temporally separates these divergent responses, we found apoptotic signaling was preceded by a decline in c/EBP-β activity and was associated with markers of ER-stress including transient eIF2α phosphorylation, and the delayed induction of the bZIP proteins ATF4 and CHOP-10. Pretreatment with the eIF2α phosphatase inhibitor salubrinal blocked the activation of caspase-3, indicating that ER-related stress responses are integral to this transition. Delivery of either full-length, or a transcriptionally inactive form of c/EBP-β protected cultures from hypoxic challenge, in part by inducing levels of the anti-apoptotic protein Bcl-2. These data indicate that the pathologic response in cortical neurons induced by hypoxia involves both the loss of c/EBP-β-mediated survival signals and activation of pro-death pathways originating from the endoplasmic reticulum.

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Endoplasmic Reticulum Stress Inhibition Protects against Excitotoxic Neuronal Injury in the Rat Brain

Cited by 292 publications

References 45 publications

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

The endoplasmic reticulum stress inhibitor salubrinal inhibits the activation of autophagy and neuroprotection induced by brain ischemic preconditioning

Loss of c/EBP-β activity promotes the adaptive to apoptotic switch in hypoxic cortical neurons

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