PMID- 37216506
OWN - NLM
STAT- MEDLINE
DCOM- 20230530
LR  - 20230605
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 120
IP  - 22
DP  - 2023 May 30
TI  - ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology 
      through FXR1-dependent BACE1 translation initiation.
PG  - e2220148120
LID - 10.1073/pnas.2220148120 [doi]
LID - e2220148120
AB  - 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.
FAU - Zhou, Gui-Feng
AU  - Zhou GF
AUID- ORCID: 0000-0002-5427-3632
AD  - Department of Neurology, the First Affiliated Hospital of Chongqing Medical 
      University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, 
      Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
FAU - Tang, Jing
AU  - Tang J
AD  - Department of Neurology, the First Affiliated Hospital of Chongqing Medical 
      University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, 
      Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
FAU - Ma, Yuan-Lin
AU  - Ma YL
AD  - Department of Neurology, the First Affiliated Hospital of Chongqing Medical 
      University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, 
      Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
FAU - Fu, Xian
AU  - Fu X
AD  - Center for Novel Target & Therapeutic Intervention, Institute of Life Sciences, 
      Chongqing Medical University, Chongqing 400016, China.
FAU - Liu, Jun-Yan
AU  - Liu JY
AUID- ORCID: 0000-0002-3018-0335
AD  - Center for Novel Target & Therapeutic Intervention, Institute of Life Sciences, 
      Chongqing Medical University, Chongqing 400016, China.
FAU - Yang, Ren-Zhi
AU  - Yang RZ
AUID- ORCID: 0009-0003-3113-882X
AD  - Institute for Brain Science and Disease, Chongqing Medical University, Chongqing 
      400016, China.
FAU - Zhang, Hong-Sheng
AU  - Zhang HS
AD  - Institute for Brain Science and Disease, Chongqing Medical University, Chongqing 
      400016, China.
FAU - Cai, Xiang-Hai
AU  - Cai XH
AD  - State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming 
      Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
FAU - Wang, Jing-Wen
AU  - Wang JW
AD  - Department of Neurology, the First Affiliated Hospital of Chongqing Medical 
      University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, 
      Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
FAU - Xie, Xiao-Yong
AU  - Xie XY
AD  - Department of Neurology, the First Affiliated Hospital of Chongqing Medical 
      University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, 
      Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
FAU - Song, Li
AU  - Song L
AD  - Department of Neurology, the First Affiliated Hospital of Chongqing Medical 
      University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, 
      Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
FAU - Luo, Biao
AU  - Luo B
AD  - Department of Neurology, the First Affiliated Hospital of Chongqing Medical 
      University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, 
      Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
FAU - Chen, Jian
AU  - Chen J
AD  - Department of Neurology, the First Affiliated Hospital of Chongqing Medical 
      University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, 
      Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
FAU - Chen, Long
AU  - Chen L
AUID- ORCID: 0009-0008-2655-5617
AD  - Department of Neurology, the First Affiliated Hospital of Chongqing Medical 
      University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, 
      Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
FAU - Deng, Xiao-Juan
AU  - Deng XJ
AD  - Department of Neurology, the First Affiliated Hospital of Chongqing Medical 
      University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, 
      Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
FAU - Chen, Guo-Jun
AU  - Chen GJ
AD  - Department of Neurology, the First Affiliated Hospital of Chongqing Medical 
      University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, 
      Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230522
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (5' Untranslated Regions)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (Bace1 protein, mouse)
RN  - 0 (Fmr1 protein, mouse)
RN  - 139135-51-6 (Fragile X Mental Retardation Protein)
RN  - 0 (Arl6ip1 protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - 5' Untranslated Regions
MH  - *Alzheimer Disease/drug therapy/genetics/metabolism
MH  - Amyloid Precursor Protein Secretases/genetics/metabolism
MH  - Aspartic Acid Endopeptidases/genetics/metabolism
MH  - Chromatography, Liquid
MH  - Fragile X Mental Retardation Protein/genetics
MH  - Protein Biosynthesis
MH  - Tandem Mass Spectrometry
PMC - PMC10235968
OTO - NOTNLM
OT  - 5'UTR
OT  - ARL6IP1
OT  - BACE1 translation
OT  - FXR1
OT  - conophylline
COIS- Conophylline has been patented by China National Intellectual Property 
      Administration.
EDAT- 2023/05/22 19:11
MHDA- 2023/05/24 06:42
PMCR- 2023/05/22
CRDT- 2023/05/22 15:13
PHST- 2023/05/24 06:42 [medline]
PHST- 2023/05/22 19:11 [pubmed]
PHST- 2023/05/22 15:13 [entrez]
PHST- 2023/05/22 00:00 [pmc-release]
AID - 202220148 [pii]
AID - 10.1073/pnas.2220148120 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2023 May 30;120(22):e2220148120. doi: 
      10.1073/pnas.2220148120. Epub 2023 May 22.