ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation

作者全名："Zhou, Gui-Feng; Tang, Jing; Ma, Yuan-Lin; Fu, Xian; Liu, Jun-Yan; Yang, Ren-Zhi; Zhang, Hong-Sheng; Cai, Xiang-Hai; Wang, Jing-Wen; Xie, Xiao-Yong; Song, Li; Luo, Biao; Chen, Jian; Chen, Long; Deng, Xiao-Juan; Chen, Guo-Jun"

作者地址："[Zhou, Gui-Feng; Tang, Jing; Ma, Yuan-Lin; Wang, Jing-Wen; Xie, Xiao-Yong; Song, Li; Luo, Biao; Chen, Jian; Chen, Long; Deng, Xiao-Juan; Chen, Guo-Jun] Chongqing Med Univ, Dept Neurol, Chongqing Key Lab Major Neurol & Mental Disorders, Chongqing Key Lab Neurol,Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Fu, Xian; Liu, Jun-Yan] Chongqing Med Univ, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, Chongqing 400016, Peoples R China; [Yang, Ren-Zhi; Zhang, Hong-Sheng] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing 400016, Peoples R China; [Cai, Xiang-Hai] Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Chi, Kunming 650201, Peoples R China"

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

来源：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

ESI学科分类：Multidisciplinary

WOS号：WOS:001038068000003

JCR分区：Q1

影响因子：9.4

年份：2023

卷号：120

期号：22

开始页：　

结束页：　

文献类型：Article

关键词：conophylline; ARL6IP1; 5'UTR; FXR1; BACE1 translation

摘要："Exploring the potential lead compounds for Alzheimer's disease (AD) remains one of the challenging tasks. Here, we report that the plant extract conophylline (CNP) impeded amyloidogenesis by preferentially inhibiting BACE1 translation via the 5' untranslated region (5'UTR) and rescued cognitive decline in an animal model of APP/PS1 mice. ADP-ribosylation factor-like protein 6-interacting protein 1 (ARL6IP1) was then found to mediate the effect of CNP on BACE1 translation, amyloidogenesis, glial activation, and cognitive function. Through analysis of the 5'UTR-targetd RNA-binding proteins by RNA pulldown combined with LC-MS/MS, we found that FMR1 autosomal homolog 1 (FXR1) interacted with ARL6IP1 and mediated CNP-induced reduction of BACE1 by regulating the 5'UTR activity. Without altering the protein levels of ARL6IP1 and FXR1, CNP treatment promoted ARL6IP1 interaction with FXR1 and inhibited FXR1 binding to the 5'UTR both in vitro and in vivo. Collectively, CNP exhibited a therapeutic potential for AD via ARL6IP1. Through pharmacological manipulation, we uncovered a dynamic interaction between FXR1 and the 5'UTR in translational control of BACE1, adding to the understanding of the pathophysiology of AD."

基金机构："Han at Hebei University of Science and Technology; NSFC [81971030,82271461]; Chongqing Education commission [KJZD-K201900404]"

基金资助正文："We sincerely thank Dr. C.-Y. Han at Hebei University of Science and Technology for providing VN-dEcCas6-VC and actin-8xCBS plas-mids. This work was supported by NSFC (81971030,82271461) and Chongqing Education commission (KJZD-K201900404) to G.-J.C."