RNF146 Inhibits Excessive Autophagy by Modulating the Wnt-β-Catenin Pathway in Glutamate Excitotoxicity Injury

Yang, Yuefan; Luo, Peng; Xu, Haoxiang; Dai, Shuhui; Rao, Wei; Peng, Cheng; Ma, Wenke; Wang, Jiu; Xu, Hao; Zhang, Lei; Zhang, Sai; Fei, Zhou

doi:10.3389/fncel.2017.00059

Cited by 22 publications

(13 citation statements)

References 43 publications

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“…These results indicated that autophagy is beneficial for cells against oxidative stress. Conversely, recent studies found that treatment with 3-MA protected HT-22 cells against glutamate-induced oxidative stress (Yang et al, 2017 ). The inconsistency between our results and previous studies might partially be attributed to different models and time points.…”

Section: Discussionmentioning

confidence: 93%

Homer1a Attenuates Hydrogen Peroxide-Induced Oxidative Damage in HT-22 Cells through AMPK-Dependent Autophagy

Luo

Rao

et al. 2018

Front. Neurosci.

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Neuronal oxidative stress is involved in diverse neurological disorders. Homer1a, as an important member of the Homer family and localized at the postsynaptic density, is known to protect cells against oxidative injury. However, the exact neuroprotective mechanism of Homer1a has not been fully elucidated. Here, we found that Homer1a promoted cell viability and reduced H2O2-induced LDH release. The overexpression of Homer1a enhanced autophagy after H2O2 treatment, which was confirmed by increased expression of LC3II, Beclin-1, and greater autophagosome formation. In addition, we demonstrated that activating autophagy improved cell survival and reduced H2O2-induced oxidative stress and mitochondrial damage. Moreover, the autophagy inhibitor 3-MA partially prevented the protective effects of Homer1a against oxidative challenge. We also found that the upregulation of Homer1a after H2O2 treatment increased the phosphorylation of AMPK. Furthermore, the AMPK inhibitor compound C inhibited Homer1a-induced autophagy and abolished Homer1a-mediated neuroprotection. All the above data suggests that Homer1a confers protection against H2O2-induced oxidative damage via AMPK-dependent autophagy.

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Section: Discussionmentioning

confidence: 93%

Homer1a Attenuates Hydrogen Peroxide-Induced Oxidative Damage in HT-22 Cells through AMPK-Dependent Autophagy

Luo

Rao

et al. 2018

Front. Neurosci.

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“…The reaction was stopped by adding 0.4 mol/l of NaOH. Activity of LDH was calculated from absorbance at 440 nm, and the background absorbance from the culture medium that was not used for cell culture was subtracted from all absorbance measurements ( 22 , 23 ).…”

Section: Methodsmentioning

confidence: 99%

Leptin Maintained Zinc Homeostasis Against Glutamate-Induced Excitotoxicity by Preventing Mitophagy-Mediated Mitochondrial Activation in HT22 Hippocampal Neuronal Cells

Jin

Hóng

2018

Front. Neurol.

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Developmental seizure-induced long-term neuronal hyperexcitation is partially mediated by regenerative mossy fiber sprouting in hippocampus. Yet, there are no effective drugs available to block this pathological process. Recently, leptin has been shown to prevent the sprouting of hippocampal mossy fibers and abnormalities in the neurobehavioral parameters. However, their underlying molecular mechanisms are largely unknown. The purpose of this study was to determine the effect of glutamate on the parameters of zinc homeostasis, mitochondrial functions, and mitophagy regulating factors, as well as to investigate the protective effects of leptin against cytotoxicity of glutamate in murine HT22 hippocampal neuronal cells. Cells were assigned to one of the four groups as follows: control group, leptin alone group, glutamate injury group, and leptin pretreatment group. Our results demonstrated that glutamate induced a decrease in superoxide dismutase, GSH (glutathione), and mitochondrial membrane potential and an increase in GSSG (oxidized glutathione), mitochondrial reactive oxygen species, and supplementation of leptin blocked the toxic effect of glutamate on cell survival. The glutamate-induced cytotoxicity was associated with an increase in mitophagy and intracellular zinc ion levels. Furthermore, glutamate activated the mitophagy markers PINK1, Parkin, and the ratio of LC3-II/LC3-I, as well as increased the expression of zinc transporter 3 (ZnT3). Leptin corrected these glutamate-caused alterations. Finally, the mitophagy inhibitor, CsA, significantly reduced intracellular zinc ion content and ZnT3 expression. These results suggest that mitophagy-mediated zinc dyshomeostasis and mitochondrial activation contributed to glutamate-induced HT22 neuronal cell injury and that leptin treatment could counteract these detrimental effects, thus highlighting mitophagy-mediated zinc homeostasis via mitochondrial activation as a potential strategy to counteract neuroexcitotoxicity.

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“…Similarly, autophagy was required for the regeneration of astrocytic mitochondrial function during inflammation in the CNS (Motori et al, ). However, excessive autophagy led to the damage of cultured HT22 cells, hippocampal neurons, and striatal neurons after excitotoxicity induced by glutamate, NMDA, or kainic acid (Dong et al, ; Wang et al, ; Yang et al, ). In our study, glutamate exposure inhibited autophagy as confirmed by the change in the LC3‐II/I ratio, p62 expression, and Beclin‐1 levels in cultured astrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Excitotoxicity and neuroinflammation are intimately linked to autophagic dysfunction (Ginet et al, 2014;Wang et al, 2017;Yang et al, 2017). In the peripheral nervous system, autophagy prevented inflammation and autophagic inhibition promoted inflammation-induced tissue injury (Kimura, Isaka, & Yoshimori, 2017;Macias-Ceja et al, 2017).…”

Section: Astrocyte Activation Is Accompanied By Lowlevel Autophagymentioning

confidence: 99%

Activation of G protein‐coupled receptor 30 protects neurons by regulating autophagy in astrocytes

Wang

Yue

et al. 2019

Glia

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Ischemic stroke leads to neuronal damage induced by excitotoxicity, inflammation, and oxidative stress. Astrocytes play diverse roles in stroke and ischemia‐induced inflammation, and autophagy is critical for maintaining astrocytic functions. Our previous studies showed that the activation of G protein‐coupled receptor 30 (GPR30), an estrogen membrane receptor, protected neurons from excitotoxicity. However, the role of astrocytic GPR30 in maintaining autophagy and neuroprotection remained unclear. In this study, we found that the neuroprotection induced by G1 (GPR30 agonist) in wild‐type mice after a middle cerebral artery occlusion was completely blocked in GPR30 conventional knockout (KO) mice but partially attenuated in astrocytic or neuronal GPR30 KO mice. In cultured primary astrocytes, glutamate exposure induced astrocyte proliferation and decreased astrocyte autophagy by activating mammalian target of rapamycin (mTOR) and c‐Jun N‐terminal kinase (JNK) and inhibiting p38 mitogen‐activated protein kinase (MAPK) pathway. G1 treatment restored autophagy to its basal level by regulating the p38 pathway but not the mTOR and JNK signaling pathways. Our findings revealed a key role of GPR30 in neuroprotection via the regulation of astrocyte autophagy and support astrocytic GPR30 as a potential drug target against ischemic brain damage.

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RNF146 Inhibits Excessive Autophagy by Modulating the Wnt-β-Catenin Pathway in Glutamate Excitotoxicity Injury

Cited by 22 publications

References 43 publications

Homer1a Attenuates Hydrogen Peroxide-Induced Oxidative Damage in HT-22 Cells through AMPK-Dependent Autophagy

Homer1a Attenuates Hydrogen Peroxide-Induced Oxidative Damage in HT-22 Cells through AMPK-Dependent Autophagy

Leptin Maintained Zinc Homeostasis Against Glutamate-Induced Excitotoxicity by Preventing Mitophagy-Mediated Mitochondrial Activation in HT22 Hippocampal Neuronal Cells

Activation of G protein‐coupled receptor 30 protects neurons by regulating autophagy in astrocytes

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