ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation.
ARL6IP1 mediates small-molecule-induced alleviation of Alzheimer pathology through FXR1-dependent BACE1 translation initiation.
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DOI：
10.1073/pnas.2220148120
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发表时间：
2023-05-30
影响因子：
11.1
通讯作者：
Chen, Guo-Jun
中科院分区：
文献类型：
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作者：
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
在阿尔茨海默病（AD）中，BACE 1将关键分子改变与毒性Aβ过载联系起来，对BACE 1的药理学调节可能有助于发现新的机制。我们报道了这样一个小分子的Conophylline（CNP），它通过5′非翻译区（5′UTR）抑制BACE 1的翻译。通过其靶点ARL 6 IP 1介导，脑穿透CNP减弱APP/PS1小鼠中的淀粉样蛋白生成并挽救认知下降。CNP处理后，ARL 6 IP 1与FXR 1（被鉴定为5′ UTR靶向蛋白）的相互作用增强，可将FXR 1与5′UTR隔离，导致BACE 1的翻译减少。总的来说，虽然CNP通过ARL 6 IP 1表现出治疗AD的潜力，但强调了BACE 1翻译控制中的动态FXR 1-RNA相互作用。寻找治疗阿尔茨海默病（AD）的先导化合物仍是一个具有挑战性的课题。在此，我们报道了植物提取物Conophylline（CNP）通过优先抑制BACE 1的5′非翻译区（5′UTR）翻译来阻止淀粉样蛋白的生成，并在APP/PS1小鼠的动物模型中挽救了认知能力的下降。然后发现ADP-核糖基化因子样蛋白6相互作用蛋白1（ARL 6 IP 1）介导CNP对BACE 1翻译、淀粉样蛋白生成、神经胶质活化和认知功能的影响。通过RNA pulldown结合LC-MS/MS分析5′ UTR靶向RNA结合蛋白，发现FMR 1常染色体同源物1（FXR 1）与ARL 6 IP 1相互作用，通过调节5′UTR活性介导CNP诱导的BACE 1减少。在不改变ARL 6 IP 1和FXR 1蛋白水平的情况下，CNP处理促进了ARL 6 IP 1与FXR 1的相互作用，并在体外和体内抑制了FXR 1与5′UTR的结合。总体而言，CNP通过ARL 6 IP 1表现出治疗AD的潜力。通过药理学操作，我们发现了FXR 1和BACE 1翻译控制中的5′UTR之间的动态相互作用，增加了对AD病理生理学的理解。
In Alzheimer’s disease (AD), BACE1 links the key molecular alterations with toxic Aβ overload, and pharmacological regulation of BACE1 may facilitate the discovery of novel mechanisms. We report such a small-molecule conophylline (CNP) that inhibits BACE1 translation through the 5′ untranslated region (5′UTR). Mediated by its target ARL6IP1, the brain-penetrating CNP attenuates amyloidogenesis and rescues cognitive decline in APP/PS1 mice. Upon CNP treatment, an enhanced interaction of ARL6IP1 with FXR1, which is identified as the 5′UTR-targeted protein, allows to sequester FXR1 from the 5′UTR, leading to the reduced translation of BACE1. Collectively, whereas CNP exhibits a therapeutic potential for AD through ARL6IP1, a dynamic FXR1–RNA interaction in the translational control of BACE1 is highlighted. 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.
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影响因子：
--
作者：
Cummings J;Fox N
通讯作者：
Fox N
影响因子：
15.1
作者：
Chami L;Checler F
通讯作者：
Checler F
影响因子：
15.3
作者：
Hu, Xiangyou;Das, Brati;Yan, Riqiang
通讯作者：
Yan, Riqiang
影响因子：
16.2
作者：
Bai, Bing;Wang, Xusheng;Peng, Junmin
通讯作者：
Peng, Junmin
影响因子：
2.5
作者：
Huang, Hsing-Yen;Dai, En-Sheng;Tsai, Huai-Jen
通讯作者：
Tsai, Huai-Jen