Downregulated AEG-1 together with inhibited PI3K/Akt pathway is associated with reduced viability of motor neurons in an ALS model

Yin, Xiang; Ren, Ming; Jiang, Hai-Zhi; Cui, Shangjin; Wang, Shuyu; Jiang, Haiyang; Yan, Qi; Wang, Jing; Wang, Xudong; Dong, Guangtao; Leeds, Peter; Chuang, De‐Maw; Feng, Honglin

doi:10.1016/j.mcn.2015.08.009

Cited by 52 publications

(45 citation statements)

References 45 publications

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“…Hence, following this hypothesis, TNFi could limit the progression of ALS . However, on the other hand, TNFα induces activation of the major survival PI3K/Akt pathway, as demonstrated in hepatocytes , and appears to be involved in motor neuron survival, as demonstrated in vivo and in vitro . TNFi may reduce the major survival pathways in motor neurons (i.e.…”

Section: Discussionmentioning

confidence: 96%

Is TNF inhibitor exposure a risk factor for amyotrophic lateral sclerosis?

Petitpain

Devos

Bagheri

et al. 2019

Fundamemntal Clinical Pharma

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TNFα modulation has been reported to be either beneficial or detrimental in amyotrophic lateral sclerosis (ALS) and therefore appears as a key issue. We analysed the relationship between TNFα inhibitor (TNFi) exposure and ALS. We performed descriptive analysis of ALS reports in patients treated with TNFi, registered in the French Pharmacovigilance Database (FPvD) and disproportionality analyses by the ‘case’/’non‐case’ method in FPvD and worldwide database (Vigibase®). The 8 retrieved ALS cases from the FPvD were 5 with limb‐onset and 3 with bulbar‐onset forms, in patients aged 43–75 years old, mainly treated for inflammatory rheumatism. The time to onset of the first symptoms ranged from 12 to 108 months, and the cumulative TNFi exposure before the diagnosis ranged from 12 to 120 months. TNFi was discontinued and thereafter survival ranged between 12 and 20 months. Disproportionality analyses showed significant associations between TNFi exposure and ALS in the FPvD and Vigibase® (160 ALS cases), regardless comparators. A putative association between TNFi and ALS must be interpreted cautiously, but TNFi could act as a predisposing or risk factor. TNFi should therefore be avoided in patients with a known risk of ALS and discontinued in the case of neurological signs of ALS.

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Section: Discussionmentioning

confidence: 96%

Is TNF inhibitor exposure a risk factor for amyotrophic lateral sclerosis?

Petitpain

Devos

Bagheri

et al. 2019

Fundamemntal Clinical Pharma

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“…AEG-1 is upregulated in NSC34 cells following activation of the PI3-K signaling pathway [16]. Therefore, we hypothesized that HIV-1 Tat upregulated AEG-1 expression in astrocytes via the PI3-K signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…According to tumor cell studies, AEG-1 positively activates NF-κB to downregulate EAAT-2 expression [11, 12], phosphorylates serine/threonine kinase (Akt), and contributes to infiltration and metastasis of tumor cells [13, 14, 15]. Interestingly, activation of the phosphatidylinositol-3-kinase/threonine kinase (PI3K/Akt) signaling pathway can upregulate AEG-1 expression in astrocytes [16]. The present study aimed to further analyze the correlation between AEG-1 and EAAT-2 expression patterns and to uncover specific molecular mechanisms underlying HAND at the tissue and cellular level.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Tat inhibits EAAT-2 through AEG-1 upregulation in models of HIV-associated neurocognitive disorder

Xiang

Zheng

et al. 2017

Oncotarget

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During HIV-associated neurocognitive disorder (HAND), decreasing in excitatory amino acid transporter 2 (EAAT-2) in astrocyte plasma membranes leads to elevated levels of extracellular glutamate and, in turn, neuronal apoptosis. We used immunohistochemistry, western blot, qRT-PCR, and RNA interference to elucidate the molecular mechanisms underlying the decreased EAAT-2 expression during HAND at the tissue and cellular levels. We used simian immunodeficiency virus-human immunodeficiency virus chimeric virus (SHIV)-infected macaques as an in vivo model of HAND. Our results show that EAAT-2 expression was decreased in the cerebral cortex, while AEG-1 expression was increased, and the expression levels of these proteins were negatively correlated. In vitro analyses showed that HIV-1 Tat inhibited EAAT-2 expression by inducing overexpression of AEG-1. More specifically, HIV-1 Tat increased AEG-1 expression via the PI3-K signaling pathway, while increasing EAAT-2 inhibition by YinYan-1 (YY-1) via the NF-κB signaling pathway. These results warrant testing AEG-1 as a potential therapeutic target for treating HAND.

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“…In line with those latter results, our group found that AEG‐1 is expressed in motor neurons of C57BL/6 mice, while in the hSOD1 G93A transgenic mice, an amyotrophic lateral sclerosis (ALS) mouse model, expression of AEG‐1 in motor neurons of the spinal anterior horn is significantly reduced. Further, we demonstrated that decreased expression of AEG‐1 induced by mutant hSOD1 was responsible for decreased neuronal viability in ALS (Yin et al, ). As AEG‐1 was able to protect PHFAs from death induced by serum starvation, through induction of the PI3K/Akt signaling, expression of AEG‐1 could be critical for neuronal survival under stress (Lee et al, ).…”

Section: Overview Of Aeg‐1mentioning

confidence: 91%

Roles of AEG‐1 in CNS neurons and astrocytes during noncancerous processes

Yin

Feng

2017

J of Neuroscience Research

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Since its initial identification, Astrocyte Elevated Gene-1 (AEG-1) has been recognized as a "star" gene detected in most of the analyzed cancers; AEG-1 can interact with signaling transduction molecules, such as PI3K/Akt and MAPK, to affect the function and viability of cells. Furthermore, its multiple other functions are also gradually being recognized. AEG-1 participates in several biological processes, including embryonic development, glutamate excitotoxicity, inflammation, and endoplasmic reticulum stress. Most of the noncancerous roles of the AEG-1 were identified in studies of the neurological disorders of the CNS. As an oncogene that promotes aberrant cellular processes within the CNS, AEG-1 may also represent an important therapeutic target for the treatment of neurological disease. However, the exact role of the AEG-1 in CNS under normal conditions is still unknown. This review will focus on the literature describing the role of this molecule in CNS neurons and astrocytes during noncancerous processes. © 2017 Wiley Periodicals, Inc.

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Downregulated AEG-1 together with inhibited PI3K/Akt pathway is associated with reduced viability of motor neurons in an ALS model

Cited by 52 publications

References 45 publications

Is TNF inhibitor exposure a risk factor for amyotrophic lateral sclerosis?

Is TNF inhibitor exposure a risk factor for amyotrophic lateral sclerosis?

HIV-1 Tat inhibits EAAT-2 through AEG-1 upregulation in models of HIV-associated neurocognitive disorder

Roles of AEG‐1 in CNS neurons and astrocytes during noncancerous processes

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