title: 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.
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Qianrong Road 20, Wuxi, 214063, Jiangsu, China. wangke@jsinm.org.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Qianrong Road 20, Wuxi, 214063, Jiangsu, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Qianrong Road 20, Wuxi, 214063, Jiangsu, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Faculty of Pharmacy, University of Sydney, Room 104 Medical Foundation Building K25, Sydney, NSW, 2006, Australia. fanfan.zhou@sydney.edu.au.
authors.forename: Fanfan
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Save Sight Institute, University of Sydney, Sydney, NSW, 2000, Australia.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhu
mesh_terms: D001932:Brain Neoplasms / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005470:Fluorometry; D058851:GPI-Linked Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018797:Cell Cycle Proteins; C096192:GAS1 protein, human; D058851:GPI-Linked Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D053453:Caspase 9
keywords: Glial cell-derived neurotrophic factor; Growth arrest-specific 1; Neurodegenerative disease; SH-SY5Y cells