title: Downregulated AEG-1 together with inhibited PI3K/Akt pathway is associated with reduced viability of motor neurons in an ALS model.
abstract: Astrocyte elevated gene-1 (AEG-1) has been reported to regulate the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and is also regulated by it. This study investigated how AEG-1 participates in the survival pathway of motor neurons in amyotrophic lateral sclerosis (ALS). We found reduced levels of AEG-1 in ALS motor neurons, both in vivo and in vitro, compared to wild type controls. Moreover, AEG-1 silencing demonstrated inhibition of the PI3K/Akt pathway and increased cell apoptosis. Additionally, the PI3K/Akt pathway in mSOD1 cells was unresponsive under serum deprivation conditions compared to wtSOD1 cells. These results suggest that AEG-1 deficiency, together with the inhibited PI3K/Akt pathway was associated with decreased viability of ALS motor neurons. However, the mRNA levels of AEG-1 were still lower in mSOD1 cells compared to the control groups, though the signaling pathway was activated by application of a PI3-K activator. This suggests that in ALS motor neurons, some unknown interruption exists in the PI3K/Akt/CREB/AEG-1 feedback loop, thus attenuating the protection by this signaling pathway. Together, these findings support that AEG-1 is a critical factor for cell survival, and the disrupted PI3K/Akt/CREB/AEG-1cycle is involved in the death of injured motor neurons and pathogenesis of ALS.
authors: Neurology Department, The First Clinical College of Harbin Medical University, Harbin 150001, PR China.
authors: Xiang
authors: X
authors: Yin
authors: Department of Neurology, The Affiliated Hospital of Weifang Medical University, Weifang 261000, Shandong, PR China.
authors: Ming
authors: M
authors: Ren
authors: Neurology Department, The First Clinical College of Harbin Medical University, Harbin 150001, PR China.
authors: Haizhi
authors: H
authors: Jiang
authors: Division of Swine Infectious Diseases, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute of Chinese Academy of Agricultural Sciences, Harbin 150001, PR China.
authors: Shangjin
authors: S
authors: Cui
authors: Neurology Department, The First Clinical College of Harbin Medical University, Harbin 150001, PR China.
authors: Shuyu
authors: S
authors: Wang
authors: Neurology Department, The First Clinical College of Harbin Medical University, Harbin 150001, PR China.
authors: Hongquan
authors: H
authors: Jiang
authors: Neurology Department, The First Clinical College of Harbin Medical University, Harbin 150001, PR China.
authors: Yan
authors: Y
authors: Qi
authors: Neurology Department, The First Clinical College of Harbin Medical University, Harbin 150001, PR China.
authors: Jing
authors: J
authors: Wang
authors: Neurology Department, The First Clinical College of Harbin Medical University, Harbin 150001, PR China.
authors: Xudong
authors: X
authors: Wang
authors: Neurology Department, The First Clinical College of Harbin Medical University, Harbin 150001, PR China.
authors: Guangtao
authors: G
authors: Dong
authors: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1363, USA.
authors: Peter
authors: P
authors: Leeds
authors: Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1363, USA.
authors: De-Maw
authors: DM
authors: Chuang
authors: Neurology Department, The First Clinical College of Harbin Medical University, Harbin 150001, PR China. Electronic address: fenghonglin1120@sina.com.
authors: Honglin
authors: H
authors: Feng
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004622:Embryo, Mammalian; D005260:Female; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D013482:Superoxide Dismutase; C079240:Mtap2 protein, mouse; C483038:Mtdh protein, mouse; C109415:SOD1 G93A protein
keywords: Amyotrophic lateral sclerosis (ALS); Astrocyte elevated gene-1 (AEG-1); CREB; PI3K/Akt pathway