STAU1 exhibits a dual function by promoting amyloidogenesis and tau phosphorylation in cultured cells

作者全名：Li, Chen-Lu; Zhou, Gui-Feng; Xie, Xiao-Yong; Wang, Lu; Chen, Xue; Pan, Qiu-Ling; Pu, Ya-Lan; Yang, Jie; Song, Li; Chen, Guo-Jun

作者地址：[Li, Chen-Lu; Zhou, Gui-Feng; Xie, Xiao-Yong; Wang, Lu; Chen, Xue; Pan, Qiu-Ling; Pu, Ya-Lan; Yang, Jie; Song, Li; Chen, Guo-Jun] Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing Key Lab Neurol, 1 Youyi Rd, Chongqing 400016, Peoples R China

通信作者：Chen, GJ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Neurol, Chongqing Key Lab Neurol, 1 Youyi Rd, Chongqing 400016, Peoples R China.

来源：EXPERIMENTAL NEUROLOGY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001241163600001

JCR分区：Q1

影响因子：4.6

年份：2024

卷号：377

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：STAU1; Alzheimer's disease; BACE1; 3'UTR; GADD45B; Tau phosphorylation

摘要：Staufen-1 (STAU1) is a double-stranded RNA-binding protein (RBP) involved in a variety of pathological conditions. In this study, we investigated the potential role of STAU1 in Alzheimer's disease (AD), in which two hallmarks are well-established as cerebral ss-amyloid protein (A ss) deposition and Tau-centered neurofibrillary tangles. We found that STAU1 protein level was significantly increased in cells that stably express full-length APP and the brain of APP/PS1 mice, an animal model of AD. STAU1 knockdown, as opposed to overexpression, significantly decreased the protein levels of ss-amyloid converting enzyme 1 (BACE1) and A ss. We further found that STAU1 extended the half-life of the BACE1 mRNA through binding to the 3 ' untranslated region (3'UTR). Transcriptome analysis revealed that STAU1 enhanced the expression of growth arrest and DNA damage 45 ss (GADD45B) upstream of P38 MAPK signaling, which contributed to STAU1-induced regulation of Tau phosphorylation at Ser396 and Thr181. Together, STAU1 promoted amyloidogenesis by inhibiting BACE1 mRNA decay, and augmented Tau phosphorylation through activating GADD45B in relation to P38 MAPK. Targeting STAU1 that acts on both amyloidogenesis and tauopathy may serve as an optimistic approach for AD treatment.

基金机构：NSFC [81971030, 82271461]

基金资助正文：<BOLD>Funding</BOLD> This work was supported by NSFC (81971030, 82271461) to G -J Chen.