title: Potential of GRID2 receptor gene for preventing TNF-induced neurodegeneration in autism.
abstract: Autism is one of the most common subtypes of autism spectrum disorder (ASD). Recent studies suggested a relationship between immune-dependent coding genes and ASD, indicating that long term neuroimmunological anomalies affect brain development and synaptic transmission among neural networks. Furthermore, various studies focused on biomarker potential of TNF-α in autism. Ionotropic receptors are also studied as potential marker for autism since altered gene expression levels are observed in autistic patients. GRID2 is a candidate ionotropic receptor which is involved glutamate transfer. In this study, to propose TNF-α dependent cellular processes involved in autism aetiology in relation to GRID2 we performed a bioinformatic network analysis and identified potential pathways and genes that are involved in TNF-α induced changes at GRID2 receptor levels. As a result, we ascertained the GRID2 receptor gene as a candidate gene and further studied the association between GRID2 expression levels and TNF-induced neurodegeneration. Our bioinformatic analyses and experimental results revealed that TNF-α regulates GRID2 gene expression by activating Cdc42 and GOPC genes. Moreover, increased TNF-α levels leads to increase of caspase-3 protein levels triggering neuronal apoptosis leading to neuronal deficiency, which is one of the major symptoms of autism. The study is the first to show the role of TNF-α in regulation of GRID2 gene expression and its signalling pathway. As a result, GRID2 gene can be a suppressor in TNF-induced neurodegeneration which may help to understand the main factors leading to autism.
authors.affiliation: Neuroscience Program, Health Sciences Institute, Uskudar University, Istanbul, Turkey.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Kalkan
authors.affiliation: Department of Biostatistics and Medical Informatics, School of Medicine, Acıbadem University, Istanbul, Turkey.
authors.forename: İlknur Melis
authors.initials: İM
authors.lastname: Durasi
authors.affiliation: Department of Biostatistics and Medical Informatics, School of Medicine, Acıbadem University, Istanbul, Turkey.
authors.forename: Ugur
authors.initials: U
authors.lastname: Sezerman
authors.affiliation: Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Üsküdar University, Istanbul, Turkey. Electronic address: belkisatasever.arslan@uskudar.edu.tr.
authors.forename: Belkis
authors.initials: B
authors.lastname: Atasever-Arslan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019295:Computational Biology; D056726:Genetic Association Studies; D000077614:Golgi Matrix Proteins; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017470:Receptors, Glutamate / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D002352:Carrier Proteins; C434484:GOPC protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D017470:Receptors, Glutamate; D014409:Tumor Necrosis Factor-alpha; C107913:glutamate receptor delta 2; D014212:Tretinoin; D020764:cdc42 GTP-Binding Protein
keywords: ASD; Autism; GRID2; SH-SY5Y human neuroblastoma cells; TNF-α