title: O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling.
abstract: Apoptosis plays an important role in neural development and neurological disorders. In this study, we found that O-GlcNAcylation, a unique protein posttranslational modification with O-linked β-N-acetylglucosamine (GlcNAc), promoted apoptosis through attenuating phosphorylation/activation of AKT and Bad. By using co-immunoprecipitation and mutagenesis techniques, we identified O-GlcNAc modification at both Thr308 and Ser473 of AKT. O-GlcNAcylation-induced apoptosis was attenuated by over-expression of AKT. We also found a dynamic elevation of protein O-GlcNAcylation during the first four hours of cerebral ischemia, followed by continuous decline after middle cerebral artery occlusion (MCAO) in the mouse brain. The elevation of O-GlcNAcylation coincided with activation of cell apoptosis. Finally, we found a negative correlation between AKT phosphorylation and O-GlcNAcylation in ischemic brain tissue. These results indicate that cerebral ischemia induces a rapid increase of O-GlcNAcylation that promotes apoptosis through down-regulation of AKT activity. These findings provide a novel mechanism through which O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling.
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Biochemistry, Nantong University Medical School, Nantong, Jiangsu 226001, China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, United States of America.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, United States of America.|Department of Pathophysiology, Nantong University Medical School, Nantong, Jiangsu 226001, China.
authors.forename: Jin-hua
authors.initials: JH
authors.lastname: Gu
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, United States of America.
authors.forename: Chun-ling
authors.initials: CL
authors.lastname: Dai
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Biochemistry, Nantong University Medical School, Nantong, Jiangsu 226001, China.
authors.forename: Jianlan
authors.initials: J
authors.lastname: Gu
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Jin
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, United States of America.
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, United States of America.
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, United States of America.
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D006031:Glycosylation; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D051025:bcl-Associated Death Protein; D051057:Proto-Oncogene Proteins c-akt