ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation
| Autor: | Gui-Feng Zhou, Jing Tang, Yuan-Lin Ma, Xian Fu, Jun-Yan Liu, Ren-Zhi Yang, Hong-Sheng Zhang, Xiang-Hai Cai, Jing-Wen Wang, Xiao-Yong Xie, Li Song, Biao Luo, Jian Chen, Long Chen, Xiao-Juan Deng, Guo-Jun Chen |
|---|---|
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Proceedings of the National Academy of Sciences. 120 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2220148120 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|