CHOP and the endoplasmic reticulum stress response in myelinating glia

Gow, Alexander; Wrabetz, Lawrence

doi:10.1016/j.conb.2009.08.007

Cited by 63 publications

(58 citation statements)

References 32 publications

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“…In contrast, the changes of ORP150 expression showed an opposite pattern: the magnitude of ORP150 upregulation was much greater in early than in late diabetes. Consistent with previous studies [16,17,18,19,20,21,22,23,24], our results demonstrate that CHOP elicited damaging effects whilst ORP150 produced cytoprotective actions on Schwann cells and sciatic nerves. Moreover, in late diabetes, the delayed but robust increase in CHOP expression overweighed the mild increase in ORP150 expression, resulting in manifestation of the adverse effects of ER stress leading to DPN.…”

Section: Discussionsupporting

confidence: 82%

“…CHOP is present in the cytosol under non-stressed conditions, and stress leads to induction of CHOP and its accumulation in the nucleus [13]. Overexpression of CHOP has been reported to lead to cell cycle arrest and/or apoptosis [14,15], whereas knockout or knockdown of CHOP exhibits reduced apoptosis in response to ER stress [16,17,18,19]. On the other hand, oxygen-regulated protein 150 (ORP150) is an essential inducible ER resident heat-shock protein 70 (HSP70) chaperone that is induced by ER stress and hypoxia [20].…”

Section: Introductionmentioning

confidence: 99%

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CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress: A New Mechanism for Diabetic Peripheral Neuropathy

Ren

et al. 2013

Cell Physiol Biochem

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Background/Aims: Peripheral neuropathy is a frequent and severe diabetic complication characterized by progressive loss of peripheral nerve axons and manifested by pain and eventually complete loss of sensation. Effective therapy for diabetic peripheral neuropathy (DPN) is still lacking due to our limited understanding of the mechanisms for nerve injury. Methods: Here we tested the roles of endoplasmic reticulum (ER) stress and the ER stress-activated pro-apoptotic protein CHOP and anti-apoptotic protein ORP150 in DPN in a rat model of high-fat/streptozotocin diabetes and in cultured Schwann cells (SCs). Results: No significant DPN was seen in the early stage of diabetes (4 weeks following verification of diabetes). However, after prolonged diabetes (16 weeks following verification of diabetes), DPN was severely developed as reflected by slowed motor and sensory nerve conduction velocity, blunted thermal nociception, and decreased intraepidermal nerve fiber profiles in the hindpaw. Meanwhile, while it was not noticed in sciatic nerves of early diabetes, ER stress in prolonged diabetic rats was indicated by robust increases in H₂O₂ production and expression of the ER chaperon glucose-regulated protein 78 (GRP78). ORP150 expression was substantially upregulated, accompanied by mild increase in CHOP expression, resulting in a low CHOP/ORP150 ratio, in early diabetes. In contrast, with prolonged diabetes, CHOP expression exceeded ORP150 expression, resulting in an increased CHOP/ORP150 ratio. In vivo knockdown of ORP150 induced DPN in early diabetes and exacerbated the DPN after prolonged diabetes, whereas knockdown of CHOP ameliorated DPN in rats with prolonged diabetic. On the other hand, in vitro knockdown of ORP150 promoted high glucose-induced SC apoptosis, whereas knockdown of CHOP protected SCs from apoptosis. Conclusion: Taken together, we have provided evidence for the critical role of ER stress in the development of DN and also uncovered CHOP/ORP150 ratio as an important mechanism for determining neuronal apoptosis during ER stress. In the early stage of diabetes, CHOP/ORP150 ratio was relatively low favoring neuronal cell survival, whereas after prolonged diabetes, CHOP/ORP150 ratio increased resulting in apoptotic cell death leading to accelerated DPN.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress: A New Mechanism for Diabetic Peripheral Neuropathy

Ren

et al. 2013

Cell Physiol Biochem

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“…ER-stress-inducing drugs result in dedifferentiation in a differentiated thyroid cell line through a Srcmediated signaling pathway (Ulianich et al, 2008). Furthermore, it has been shown that, in a mouse model of Charcot-Marie-Tooth 1B neuropathy, CHOP expression causes Schwann cell dysfunction (demyelination or hypomyelination), but not cell death (Pennuto et al, 2008); these observations are similar to JUN-dependent Schwann cell de-differentiation after nerve injury (Parkinson et al, 2008;Gow and Wrabetz, 2009). These examples further implicate alteration of cell fate by reprogramming to a less differentiated state (which might be energetically more favorable than maintaining the differentiated state) as an adaptive strategy during ER stress.…”

Section: Adapting To and Surviving Er Stress In Vivo By Reprogrammingsupporting

confidence: 63%

In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences

Tsang

Chan

Bateman

et al. 2010

Journal of Cell Science

116

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SummaryDisturbances to the balance of protein synthesis, folding and secretion in the endoplasmic reticulum (ER) induce stress and thereby the ER stress signaling (ERSS) response, which alleviates this stress. In this Commentary, we review the emerging idea that ER stress caused by abnormal physiological conditions and/or mutations in genes that encode client proteins of the ER is a key factor underlying different developmental processes and the pathology of diverse diseases, including diabetes, neurodegeneration and skeletal dysplasias. Recent studies in mouse models indicate that the effect of ERSS in vivo and the nature of the cellular strategies induced to ameliorate pathological ER stress are crucial factors in determining cell fate and clinical disease features. Importantly, ERSS can affect cellular proliferation and the differentiation program; cells that survive the stress can become 'reprogrammed' or dysfunctional. These cellautonomous adaptation strategies can generate a spectrum of context-dependent cellular consequences, ranging from recovery to death. Secondary effects can include altered cell-extracellular-matrix interactions and non-cell-autonomous alteration of paracrine signaling, which contribute to the final phenotypic outcome. Recent reports showing that ER stress can be alleviated by chemical compounds suggest the potential for novel therapeutic approaches. (1) Physiological ER stress during development is mild and controllable. The cell can recover from and/or adapt to the protein-folding stress; it can also differentiate into a specialized cell type in a manner that depends on components of ERSS and appropriate developmental signals. (2) In severe pathological ER stress, ERSS is initially an adaptive response, but, if stress remains unresolved, perhaps because of continuous and/or cyclical expression of mutant protein, it can lead to interference with developmental signals and disruption of cellular gene expression patterns. The cell can then display altered proliferation and differentiation status, and become dysfunctional. (3) Under conditions of extreme stress, an apoptotic signal is triggered and becomes dominant, leading to cell death. This can occur through excessive production of reactive oxygen species (ROS) caused by enhanced protein-folding activity, which relates to levels of CHOP, GADD34 and ERO1 expression. Journal of Cell Science Attenuation of translationOne of the early responses to ER stress is the modulation of translation, a highly conserved adaptation mechanism (Yamasaki and Anderson, 2008). Phosphorylation of eukaryotic initiation factor 2 (eIF2) by PERK reduces protein translation and shifts the translation machinery to favor alternative modes of initiation, including selective translation of activating transcription factor 4 (ATF4) . Phosphorylated eIF2 also activates the conversion of microtubule-associated protein 1 light chain 3 (LC3-I), an essential protein for autophagy, to LC3-II and hence promotes autophagosome formation Kouroku et al., 2007), as well as t...

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“…Thus, impairing Chop may remove not only maladaptive, but also adaptive effectors and produce a less complete rescue of myelination. This idea is particularly appealing because it could explain the contextdependent behavior of CHOP (Gow and Wrabetz, 2009), that is detrimental in Schwann cells (Pennuto et al, 2008), but beneficial in oligodendrocytes in a model of PelizeusMerzbacher disease (Southwood et al, 2002). The balance of adaptive and maladaptive CHOP targets may simply differ between the two cell types.…”

Section: Gadd34 Versus Chop Inactivation In S63del Myelinationmentioning

confidence: 99%

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

D’Antonio¹,

Musner²,

Scapin³

et al. 2013

J Cell Biol

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CHOP and the endoplasmic reticulum stress response in myelinating glia

Cited by 63 publications

References 32 publications

CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress: A New Mechanism for Diabetic Peripheral Neuropathy

CHOP/ORP150 Ratio in Endoplasmic Reticulum Stress: A New Mechanism for Diabetic Peripheral Neuropathy

In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences

Resetting translational homeostasis restores myelination in Charcot-Marie-Tooth disease type 1B mice

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