title: Regulation of RAGE splicing by hnRNP A1 and Tra2β-1 and its potential role in AD pathogenesis.
abstract: The receptor for advanced glycation end products (RAGE) gene expresses two major alternative splicing isoforms, full-length membrane-bound RAGE (mRAGE) and secretory RAGE (esRAGE). Both isoforms play important roles in Alzheimer's disease (AD) pathogenesis, either via interaction of mRAGE with β-amyloid peptide (Aβ) or inhibition of the mRAGE-activated signaling pathway. In the present study, we showed that heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and Transformer2β-1 (Tra2β-1) were involved in the alternative splicing of mRAGE and esRAGE. Functionally, two factors had an antagonistic effect on the regulation. Glucose deprivation induced an increased ratio of mRAGE/esRAGE via up-regulation of hnRNP A1 and down-regulation of Tra2β-1. Moreover, the ratios of mRAGE/esRAGE and hnRNP A1/Tra2β-1 were increased in peripheral blood mononuclear cells from AD patients. The results provide a molecular basis for altered splicing of mRAGE and esRAGE in AD pathogenesis. The receptor for advanced glycation end products (RAGE) gene expresses two major alternative splicing isoforms, membrane-bound RAGE (mRAGE) and secretory RAGE (esRAGE). Both isoforms play important roles in Alzheimer's disease (AD) pathogenesis. Mechanism for imbalanced expression of these two isoforms in AD brain remains elusive. We proposed here a hypothetic model to illustrate that impaired glucose metabolism in AD brain may increase the expression of splicing protein hnRNP A1 and reduce Tra2β-1, which cause the imbalanced expression of mRAGE and esRAGE.
authors.affiliation: Department of Neurobiology, Laboratory of Genomic Physiology, State Key Laboratory of Medical Neurobiology, Institutes of Brain Science, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Liu
authors.forename: Hong-Lei
authors.initials: HL
authors.lastname: Li
authors.forename: Jia-Bin
authors.initials: JB
authors.lastname: Su
authors.forename: Fei-Hong
authors.initials: FH
authors.lastname: Ding
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Fang
authors.initials: F
authors.lastname: Chai
authors.forename: Yuan-Xin
authors.initials: YX
authors.lastname: Li
authors.forename: Shi-Cao
authors.initials: SC
authors.lastname: Cui
authors.forename: Feng-Yan
authors.initials: FY
authors.lastname: Sun
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: Wu
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Xian-Hua
authors.initials: XH
authors.lastname: Chen
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology*; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005947:Glucose / Q000172:deficiency; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism*; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D007963:Leukocytes, Mononuclear; D008297:Male; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D017381:Spliceosomes / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C097083:TRA2B protein, human; C000619656:hnRNPA1 protein, human; D000068103:Serine-Arginine Splicing Factors; D005947:Glucose
keywords: Alzheimer's disease (AD); Transformer2β-1; alternative splicing; hnRNP A1; receptor for advanced glycation end products