Endoplasmic reticulum: a primary target in various acute disorders and degenerative diseases of the brain

Paschen, Wulf

doi:10.1016/s0143-4160(03)00139-8

Cited by 171 publications

(134 citation statements)

References 143 publications

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“…Endoplasmic reticulum dysfunction has been postulated as a common pathologic denominator underlying acute and chronic neurodegenerative disorders, including brain ischemia. 15,16 Therefore, we wished to test the hypothesis that aNAC depletion might lead to the activation of the UPR in the ER.…”

Section: Resultsmentioning

confidence: 99%

“…Unfolded or misfolded proteins that are not transported from the ER to the Golgi compartment may be degraded by the ubiquitin/ proteasome pathway. 15 If this phenomenon occurs in aNACdepleted cells, ubiquitin must accumulate in the cytoplasm to degrade the unfolded or misfolded proteins. 23 Therefore, we tested this possibility by the immunohistochemical detection of ubiquitin localization in aNAC-depleted cells.…”

Section: Resultsmentioning

confidence: 99%

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αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

Hotokezaka

Leyen

et al. 2009

Cell Death Differ

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Accumulation of unfolded proteins triggers endoplasmic reticulum (ER) stress and is considered a part of the cellular responses to hypoxia. The nascent polypeptide-associated complex (NAC) participates in the proper maturation of newly synthesized proteins. However, thus far, there have been no comprehensive studies on NAC involvement in hypoxic stress. Here, we show that hypoxia activates glycogen synthase kinase-3b (GSK-3b) and that the activated GSK-3b destabilizes aNAC with the subsequent apoptosis of the cell. Hypoxia of various cell types and the mouse ischemic brain was associated with rapid downregulation of aNAC and ER stress responses involving PERK, ATF4, c-taxilin, elF2a, Bip, and CHOP. Depletion of aNAC by RNA interference specifically activated ER stress responses and caused mitochondrial dysfunction, which resulted in apoptosis through caspase activation. Interestingly, we found that the hypoxic conditions activated GSK-3b, and that GSK-3b inhibition prevented aNAC protein downregulation in hypoxic cells and rescued the cells from apoptosis. In addition, aNAC overexpression increased the viability of hypoxic cells. Taken together, these results suggest that aNAC degradation triggers ER stress responses and initiates apoptotic processes in hypoxic cells, and that GSK-3b may participate upstream in this mechanism.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

Hotokezaka

Leyen

et al. 2009

Cell Death Differ

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“…Acute neurologic insults are known to cause protein misfolding and endoplasmic reticulum stress, as well as proteasomal inhibition (Paschen, 2003b;Rao et al, 2004). Endoplasmic reticulum stress can result in Puma induction (Reimertz et al, 2003), and recent work suggests that this is mediated by activating transcription factor 4 and CHOP (Galehdar et al, 2010).…”

Section: Mechanism Of Action and Relative Potency Of Bcl-2 Homology Dmentioning

confidence: 99%

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

Engel

Plesnila

Prehn

et al. 2011

J Cereb Blood Flow Metab

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The Bcl-2 homology (BH) domain 3-only proteins are a proapoptotic subgroup of the Bcl-2 gene family, which regulate cell death via effects on mitochondria. The BH3-only proteins react to various cell stressors and promote cell death by binding and inactivating antiapoptotic Bcl-2 family members and direct activation of proapoptotic multi-BH domain proteins such as Bax. Here, we review the in vivo evidence for their involvement in the pathophysiology of status epilepticus and contrast it to ischemia and traumatic brain injury. Seizures in rodents activate three potent proapoptotic BH3-only proteins: Bid, Bim, and Puma. Analysis of damage after seizures in mice singly deficient for each BH3-only protein supports a causal role for Puma and to a lesser extent Bim but, surprisingly, not Bid. In ischemia and trauma, where core aspects of the pathophysiology of cell death overlap, multiple BH3-only proteins are also activated and Bid has been shown to be required for neuronal death. The findings suggest that while each neurologic insult activates multiple BH3-only proteins, there may be specificity in their functional contribution. Future challenges include evaluating the remaining BH3-only proteins, explaining different causal contributions, and, if possible, exploring neurologic outcomes in mouse models deficient for multiple BH3-only proteins.

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“…[11][12][13][14] ER stress and the apoptotic program coupled to it have been implicated in many important pathologies, including diabetes, obesity, neurodegenerative disorders, viral infection, and a variety of ER storage diseases. 5,[15][16][17][18][19] Nevertheless, the initiation and execution steps of ER stress-induced apoptosis in mammals remain poorly understood. Classical genetics has allowed detailed dissection of the ESR in lower organisms such as Saccharomyces cerevisiae, but greater complexity and intractable genetics have hindered progress in mammalian systems.…”

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confidence: 99%

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

Boyce

Ryazanov

et al. 2008

Cell Death Differ

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Apoptosis triggered by endoplasmic reticulum (ER) stress has been implicated in many diseases but its cellular regulation remains poorly understood. Previously, we identified salubrinal (sal), a small molecule that protects cells from ER stressinduced apoptosis by selectively activating a subset of endogenous ER stress-signaling events. Here, we use sal as a probe in a proteomic approach to discover new information about the endogenous cellular response to ER stress. We show that sal induces phosphorylation of the translation elongation factor eukaryotic translation elongation factor 2 (eEF-2), an event that depends on eEF-2 kinase (eEF-2K). ER stress itself also induces eEF-2K-dependent eEF-2 phosphorylation, and this pathway promotes translational arrest and cell death in this context, identifying eEF-2K as a hitherto unknown regulator of ER stress-induced apoptosis. Finally, we use both sal and ER stress models to show that eEF-2 phosphorylation can be activated by at least two signaling mechanisms. Our work identifies eEF-2K as a new component of the ER stress response and underlines the utility of novel small molecules in discovering new cell biology. Cell Death and Differentiation (2008) 15, 589-599; doi:10.1038/sj.cdd.4402296; published online 11 January 2008 The endoplasmic reticulum (ER) serves as the primary processing site for membrane and secreted proteins. The ER recruits translating ribosomes, translocates newly synthesized polypeptides into its lumen, and promotes a variety of post-translational modifications and chaperone-facilitated protein folding. 1,2 Proper ER function is critical for numerous aspects of cell physiology, including vesicle trafficking, lipid and membrane biogenesis, and protein targeting and secretion. Accordingly, cells react rapidly to various forms of ER dysfunction -including the accumulation of unfolded, misfolded or excessive protein, ER lipid or glycolipid imbalances, or changes in the redox or ionic conditions of the ER lumenthrough a set of adaptive pathways known collectively as the ER stress response (ESR). [2][3][4][5] The ESR promotes cell survival both by increasing the capacity of the ER to fold and process client proteins and by reducing the amount of protein inside the ER. These effects are achieved through three major pathways: (1) the unfolded protein response, a transcription-dependent induction of ER lumenal chaperone proteins and many other components of the secretory apparatus, which augments the polypeptide processing capacity of the ER; 5,6 (2) the activation of proteasome-dependent ER-associated degradation to remove proteins from the ER; 7,8 and (3) the control of protein translation to modulate the polypeptide traffic into the ER. 9,10 Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger apoptosis. [11][12][13][14] ER stress and the apoptotic program coupled to it have been implicated in many important pathologies, including diabetes, obesity, neurodegenerativ...

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Endoplasmic reticulum: a primary target in various acute disorders and degenerative diseases of the brain

Cited by 171 publications

References 143 publications

αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

αNAC depletion as an initiator of ER stress-induced apoptosis in hypoxia

In vivoContributions of BH3-Only Proteins to Neuronal Death Following Seizures, Ischemia, and Traumatic Brain Injury

A pharmacoproteomic approach implicates eukaryotic elongation factor 2 kinase in ER stress-induced cell death

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