Eif-2a Protects Brainstem Motoneurons in a Murine Model of Sleep Apnea

Zhu, Yan; Fenik, Polina; Zhan, Guanxia; Sanfillipo-Cohn, Ben; Naidoo, Nirinjini; Veasey, Sigrid C.

doi:10.1523/jneurosci.5232-07.2008

Cited by 79 publications

(57 citation statements)

References 50 publications

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“…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%

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: 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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“…For example, Zhu et al (71) showed that IH -induced ER stress may cause selective damage of upper airway motoneurons in the brainstem that could explain the impaired hypoglossal nerve affecting respiratory function found in OSA. In addition, a recent study demonstrated that the CHOP level in the hippocampus was increased in mice models of OSA and it plays a role in neural injury (12).…”

Section: Discussionmentioning

confidence: 99%

Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory

Xie

Shi

et al. 2015

Antioxidants & Redox Signaling

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Aims: This study examined the role of endoplasmic reticulum (ER) stress in mediating chronic intermittent hypoxia (IH)-induced neurocognitive deficits. We designed experiments to demonstrate that ER stress is initiated in the hippocampus under chronic IH and determined its role in apoptotic cell death, impaired synaptic structure and plasticity, and memory deficits. Results: Two weeks of IH disrupted ER fine structure and upregulated ER stress markers, glucose-regulated protein 78, caspase-12, and C/EBP homologous protein, in the hippocampus, which could be suppressed by ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid. Meanwhile, ER stress induced apoptosis via decreased Bcl-2, promoted reactive oxygen species production, and increased malondialdehyde formation and protein carbonyl, as well as suppressed mitochondrial function. These effects were largely prevented by ER stress inhibitors. On the other hand, suppression of oxidative stress could reduce ER stress. In addition, the length of the synaptic active zone and number of mature spines were reduced by IH. Long-term recognition memory and spatial memory were also impaired, which was accompanied by reduced long-term potentiation in the Schaffer collateral pathway. These effects were prevented by coadministration of the TUDCA. Innovation and Conclusion: These results show that ER stress plays a critical role in underlying memory deficits in obstructive sleep apnea (OSA)-associated IH. Attenuators of ER stress may serve as novel adjunct therapeutic agents for ameliorating OSA-induced neurocognitive impairment. Antioxid. Redox Signal. 23, 695-710.

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“…In our model the initial adaptive hypoxic period (0 -6 h) was characterized by immediate early gene expression, expression of HIF1-␣ target genes, and phosphorylation of the translation initiation factor eIF2␣, which based on previous reports would confer cytoprotective effects (29). A second phase (6 -12 h) heralded by dephosphorylation of eIF2␣ and recovery from translational arrest was associated with the expression of ATF4, induction of the pro-apoptotic target TRB3, and the accumulation of cCasp3, cPARP, and nuclear condensation.…”

Section: Discussionmentioning

confidence: 99%

The Endoplasmic Reticulum Stress Response Factor CHOP-10 Protects against Hypoxia-induced Neuronal Death

Halterman

Gill

DeJesus

et al. 2010

Journal of Biological Chemistry

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Hypoxia-induced gene expression is a critical determinant of neuron survival after stroke. Understanding the cell autonomous genetic program controlling adaptive and pathological transcription could have important therapeutic implications. To identify the factors that modulate delayed neuronal apoptosis after hypoxic injury, we developed an in vitro culture model that recapitulates these divergent responses and characterized the sequence of gene expression changes using microarrays. Hypoxia induced a disproportionate number of bZIP transcription factors and related targets involved in the endoplasmic reticulum stress response. Although the temporal and spatial aspects of ATF4 expression correlated with neuron loss, our results did not support the anticipated pathological role for delayed CHOP expression. Rather, CHOP deletion enhanced neuronal susceptibility to both hypoxic and thapsigargin-mediated injury and attenuated brain-derived neurotrophic factorinduced neuroprotection. Also, enforced expression of CHOP prior to the onset of hypoxia protected wild-type cultures against subsequent injury. Collectively, these findings indicate CHOP serves a more complex role in the neuronal response to hypoxic stress with involvement in both ischemic preconditioning and delayed neuroprotection.

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Eif-2a Protects Brainstem Motoneurons in a Murine Model of Sleep Apnea

Cited by 79 publications

References 50 publications

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Sustained translational repression by eIF2α-P mediates prion neurodegeneration

Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory

The Endoplasmic Reticulum Stress Response Factor CHOP-10 Protects against Hypoxia-induced Neuronal Death

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