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SHMT2 通过 5'UTR 依赖性 ADAM10 翻译起始介导小分子诱导的阿尔茨海默病病理减轻。

SHMT2 Mediates Small-Molecule-Induced Alleviation of Alzheimer Pathology Via the 5'UTR-dependent ADAM10 Translation Initiation.

机构信息

Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.

Department of Pharmacy, Yongchuan Hospital of Chongqing Medical University, Chongqing, 402160, China.

出版信息

Adv Sci (Weinh). 2024 Mar;11(11):e2305260. doi: 10.1002/advs.202305260. Epub 2024 Jan 6.

DOI:10.1002/advs.202305260
PMID:38183387
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10953581/
Abstract

It is long been suggested that one-carbon metabolism (OCM) is associated with Alzheimer's disease (AD), whereas the potential mechanisms remain poorly understood. Taking advantage of chemical biology, that mitochondrial serine hydroxymethyltransferase (SHMT2) directly regulated the translation of ADAM metallopeptidase domain 10 (ADAM10), a therapeutic target for AD is reported. That the small-molecule kenpaullone (KEN) promoted ADAM10 translation via the 5' untranslated region (5'UTR) and improved cognitive functions in APP/PS1 mice is found. SHMT2, which is identified as a target gene of KEN and the 5'UTR-interacting RNA binding protein (RBP), mediated KEN-induced ADAM10 translation in vitro and in vivo. SHMT2 controls AD signaling pathways through binding to a large number of RNAs and enhances the 5'UTR activity of ADAM10 by direct interaction with GAGGG motif, whereas this motif affected ribosomal scanning of eukaryotic initiation factor 2 (eIF2) in the 5'UTR. Together, KEN exhibits therapeutic potential for AD by linking OCM with RNA processing, in which the metabolic enzyme SHMT2 "moonlighted" as RBP by binding to GAGGG motif and promoting the 5'UTR-dependent ADAM10 translation initiation.

摘要

一直以来，人们都认为一碳代谢（OCM）与阿尔茨海默病（AD）有关，但其潜在机制仍知之甚少。利用化学生物学，报告称线粒体丝氨酸羟甲基转移酶 2（SHMT2）可直接调节 ADAM 金属肽酶结构域 10（ADAM10）的翻译，ADAM10 是 AD 的治疗靶点。小分子 kenpaullone（KEN）通过 5'非翻译区（5'UTR）促进 ADAM10 翻译，并改善 APP/PS1 小鼠的认知功能。鉴定出 SHMT2 是 KEN 和 5'UTR 相互作用 RNA 结合蛋白（RBP）的靶基因，介导 KEN 诱导的体外和体内 ADAM10 翻译。SHMT2 通过与大量 RNA 结合来控制 AD 信号通路，并通过与 GAGGG 基序直接相互作用来增强 ADAM10 的 5'UTR 活性，而该基序影响真核起始因子 2（eIF2）在 5'UTR 中的核糖体扫描。KEN 通过将 OCM 与 RNA 处理联系起来，表现出治疗 AD 的潜力，其中代谢酶 SHMT2 通过与 GAGGG 基序结合并促进 5'UTR 依赖性 ADAM10 翻译起始，“兼职”作为 RBP。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/7af11d30980a/ADVS-11-2305260-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/dad040ab9157/ADVS-11-2305260-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/f649b0ea0246/ADVS-11-2305260-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/008a9290bfff/ADVS-11-2305260-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/ad7708d71d3c/ADVS-11-2305260-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/181b1c4d8d9c/ADVS-11-2305260-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/0412713e6bf9/ADVS-11-2305260-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/c7a8cb1d7eb4/ADVS-11-2305260-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/7af11d30980a/ADVS-11-2305260-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/dad040ab9157/ADVS-11-2305260-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/f649b0ea0246/ADVS-11-2305260-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/008a9290bfff/ADVS-11-2305260-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/ad7708d71d3c/ADVS-11-2305260-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/181b1c4d8d9c/ADVS-11-2305260-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/0412713e6bf9/ADVS-11-2305260-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/c7a8cb1d7eb4/ADVS-11-2305260-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/78b2/10953581/7af11d30980a/ADVS-11-2305260-g007.jpg

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