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

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

  • Adv Sci (Weinh). 2024 Jan 6:e2305260. doi: 10.1002/advs.202305260.
Li Song 1,  Qiu-Ling Pan 1,  Gui-Feng Zhou 1,  Sheng-Wei Liu 2,  Bing-Lin Zhu 1,  Pei-Jia Lin 1,  Xiao-Tong Hu 1 3,  Jing-Si Zha 1 4,  Yan Long 1 5,  Biao Luo 1,  Jian Chen 1,  Ying Tang 1 6,  Jing Tang 1,  Xiao-Jiao Xiang 1 7,  Xiao-Yong Xie 1,  Xiao-Juan Deng 1,  Guo-Jun Chen 1
Affiliations

Affiliations

  • 1 Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 2 Department of Pharmacy, Yongchuan Hospital of Chongqing Medical University, Chongqing, 402160, China.
  • 3 Department of Health Management, Daping Hospital, Army Medical university, Chongqing, 400042, China.
  • 4 Department of Internal Medicine, The Southwest University Hospital, Chongqing, 400715, China.
  • 5 Department of Geriatric Medicine, Daping Hospital, Army Medical university, Chongqing, 400042, China.
  • 6 Department of Neurology, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 7 Department of Nuclear Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
PMID: 38183387 DOI: 10.1002/advs.202305260
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.

Keywords

5′UTR; ADAM10; Alzheimer's disease; Kenpaullone; RNA binding protein; SHMT2; translation inhibitory element.

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