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Regulation of RAGE splicing by hn RNP A1 and Tra2β‐1 and its potential role in AD pathogenesis
Author(s) -
Liu XiaoYan,
Li HongLei,
Su JiaBin,
Ding FeiHong,
Zhao JingJing,
Chai Fang,
Li YuanXin,
Cui ShiCao,
Sun FengYan,
Wu ZhiYing,
Xu Ping,
Chen XianHua
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13069
Subject(s) - rage (emotion) , heterogeneous nuclear ribonucleoprotein , gene isoform , alternative splicing , rna splicing , pathogenesis , glycation , receptor , medicine , endocrinology , microbiology and biotechnology , biology , neuroscience , gene , rna , genetics
The receptor for advanced glycation end products ( RAGE ) gene expresses two major alternative splicing isoforms, full‐length membrane‐bound RAGE ( mRAGE ) and secretory RAGE (es RAGE ). 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 (hn RNP A1) and Transformer2β‐1 (Tra2β‐1) were involved in the alternative splicing of mRAGE and es RAGE . Functionally, two factors had an antagonistic effect on the regulation. Glucose deprivation induced an increased ratio of mRAGE /es RAGE via up‐regulation of hn RNP A1 and down‐regulation of Tra2β‐1. Moreover, the ratios of mRAGE /es RAGE and hn RNP 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 es RAGE 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.