SHMT2 Mediates Small‐Molecule‐Induced Alleviation of Alzheimer Pathology Via the 5′UTR‐dependent ADAM10 Translation Initiation

• Published in: Advanced science Vol. 11; no. 11
• Main Authors: Song, Li, Pan, Qiu‐Ling, Zhou, Gui‐Feng, Liu, Sheng‐Wei, Zhu, Bing‐Lin, Lin, Pei‐Jia, Hu, Xiao‐Tong, Zha, Jing‐Si, Long, Yan, Luo, Biao, Chen, Jian, Tang, Ying, Tang, Jing, Xiang, Xiao‐Jiao, Xie, Xiao‐Yong, Deng, Xiao‐Juan, Chen, Guo‐Jun
• Format: Journal Article
• Language: English
• Published: Weinheim John Wiley & Sons, Inc 01.03.2024; John Wiley and Sons Inc; Wiley
• Subjects: 5′UTR; ADAM10; Aging; Alzheimer's disease; Kenpaullone; Kinases; Metabolism; Metabolites; Molecular weight; Mutation; Pathogenesis; Protein synthesis; Proteins; RNA binding protein; SHMT2; translation inhibitory element
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202305260

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. SHMT2, an enzyme in mitochondrial one‐carbon metabolism, also functions as an RNA‐binding protein by interacting with the GAGGG motif in the 5’UTR of ADAM10. This interaction results in an altered 5’UTR structure that promotes ribosomal read‐through by the eIF2 complex. This mechanism enables the small molecule kenpaullone to enhance ADAM10 translation, thereby inhibiting Aβ generation associated with Alzheimer's disease.