Gas1 Knockdown Increases the Neuroprotective Effect of Glial Cell-Derived Neurotrophic Factor Against Glutamate-Induced Cell Injury in Human SH-SY5Y Neuroblastoma Cells

Abstract

Growth arrest-specific 1 (Gas1) protein acts as an inhibitor of cell growth and a mediator of cell death in nervous system during development and is also re-expressed in adult neurons during excitotoxic insult. Due to its structural similarity to the glial cell-derived neurotrophic factor family receptors α (GFRα), Gas1 is likely to interfere with the neuroprotective effect of GDNF. In the present study, we investigated the expression profile of Gas1 during glutamate insults in human SH-SY5Y neuroblastoma cells as well as the influence of Gas1 inhibition on the protective effect of GDNF against glutamate-induced cell injury. Our data showed that Gas1 expression was significantly increased with the treatment of glutamate in SH-SY5Y cells. The silencing of Gas1 by small interfering RNA promoted the protective effect of GDNF against glutamate-induced cytotoxicity as well as cell apoptosis, which effect was likely mediated through activating Akt/PI3 K-dependent cell survival signaling pathway and inhibiting mitochondrial-dependent cell apoptosis signaling pathway via Bad dephosphorylation blockade. In summary, this study showed the synergistic effect of Gas1 inhibition and GDNF against glutamate-induced cell injury in human SH-SY5Y neuroblastoma cells, which information might significantly contribute to better understanding the function of Gas1 in neuronal cells and form the basis of the therapeutic development of GDNF in treating human neurodegenerative diseases in the future.

Gas1 up-regulation is inducible and contributes to cell apoptosis in reactive astrocytes in the substantia nigra of LPS and MPTP models

“…We also confirmed the gradual elevation of Gas1 expression in the SH-SY5Y dopaminergic cells that was accompanied by apoptosis in a serum-deprived condition [ 15 ]. Gas1 knockdown increases the protective effect of GDNF against glutamate-induced injury in SH-SY5Y cells [ 23 ], and Gas1 has been reported to be induced and involved in the excitotoxic deaths of hippocampal neurons [ 16 ]. Thus, the data from the present study may also propose a critical question regarding the enrollment of the up-regulation of the Gas1 signal in the mediation of the apoptosis of dopaminergic neurons in the substantia nigra during the pathogenesis of PD.…”

Time-dependent cytokine and chemokine changes in mouse cerebral cortex following a mild traumatic brain injury

“…GAS-1 and VEGF-B were increased, and CXCL16 was reduced compared to sham levels. Of these three proteins GAS-1 and CXCL16 may be the best options for drug target validation, both proteins are known to modulate neuronal cell death involving glutamate excitotoxicity, a common feature of brain injuries ( Globus et al, 1995 ; Mellström et al, 2002 ; Rosito et al, 2012 ; Rosito et al, 2014 ; Sun et al, 2016 ; Wang et al, 2016a ; Zarco et al, 2012 ) and as such may make them ideal candidate drug targets for evaluation. While there are no direct reports of the actions of VEGF-B on the traumatized brain, it is tempting to speculate that the homeostatic and pro-neurogenesis properties of the protein would be ripe for exploration in TBI ( Nag et al, 2002 ; Sun et al, 2004 ; Sun et al, 2006 ).…”

Effects of Gas1 on gliomas: a review on current preclinical studies

“…In hippocampal neurons, Gas1 induces cell death after excitotoxic insults, inhibiting the signaling induced by GDNF. [99,100] Nevertheless, during cerebellar development Gas1 induces the proliferation of cerebellar granule neuron progenitors in a Shh-dependent manner. [71,96] …”

“…This leads to the translocation of BAD to the mitochondria and the release of cytochrome-C to the cytosol which in turn induces the activation of Caspases 9 and 3. [107,108,[115][116][117][118] Recently Wang and et al [100] demonstrated that Gas1 promotes excitotoxicity in dopaminergic neurons by inhibiting the GDNF signaling pathway.…”