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

doi:10.1073/pnas.2220148120

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	ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation
	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
	2023
Source Publication	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN	1091-6490
Volume	120 Issue:22 Pages:e2220148120
Abstract	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.
Keyword	conophylline ARL6IP1 5'UTR FXR1 BACE1 translation AMYLOID PRECURSOR PROTEIN A-BETA TRANSGENIC MICE MOUSE MODEL NEURODEGENERATION EXPRESSION REDUCTION MEMBRANE MEMORY ER
DOI	10.1073/pnas.2220148120
WOS ID	WOS:001038068000003
Citation statistics
Document Type	期刊论文
Identifier	http://ir.kib.ac.cn/handle/151853/74885
Collection	中国科学院昆明植物研究所
Recommended Citation GB/T 7714	Zhou,Gui-Feng,Tang,Jing,Ma,Yuan-Lin,et al. ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2023,120(22):e2220148120.
APA	Zhou,Gui-Feng.,Tang,Jing.,Ma,Yuan-Lin.,Fu,Xian.,Liu,Jun-Yan.,...&Chen,Guo-Jun.(2023).ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,120(22),e2220148120.
MLA	Zhou,Gui-Feng,et al."ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 120.22(2023):e2220148120.

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