Liu, Yu-JuYu-JuLiuJu, Tz-ChuenTz-ChuenJuChen, Hui-MeiHui-MeiChenJang, Yu-SungYu-SungJangLee, Li-MingLi-MingLeeLai, Hsing-LinHsing-LinLaiTai, Hua-ChiaHua-ChiaTaiFang, Jim-MinJim-MinFangLin, Yun-LianYun-LianLinTu, Pang-HsienPang-HsienTuJIM-MIN FANGHUI-MEI CHEN2020-02-272020-02-2720150964-6906https://scholars.lib.ntu.edu.tw/handle/123456789/466736TAR DNA-binding protein-43 (TDP-43) is a nuclear RNA-binding protein involved in many cellular pathways. TDP-43-positive inclusions are a hallmark of amyotrophic lateral sclerosis (ALS). The major clinical presentation of ALS is muscle weakness due to the degeneration of motor neurons. Mislocalization of TDP-43 from the nucleus to the cytoplasm is an early event of ALS. In this study, we demonstrate that cytoplasmic mislocalization of TDP-43 was accompanied by increased activation of AMP-activated protein kinase (AMPK) in motor neurons of ALS patients. The activation of AMPK in a motor neuron cell line (NSC34) or mouse spinal cords induced the mislocalization of TDP-43, recapitulating this characteristic of ALS. Down-regulation of AMPK-α1 or exogenous expression of a dominant-negative AMPK-α1 mutant reduced TDP-43 mislocalization. Suppression of AMPK activity using cAMP-simulating agents rescued the mislocalization of TDP-43 in NSC34 cells and delayed disease progression in TDP-43 transgenic mice. Our findings demonstrate that activation of AMPK-α1 plays a critical role in TDP-43 mislocalization and the development of ALS; thus, AMPK-α1 may be a potential drug target for this devastating disease. ? The Author 2014. Published by Oxford University Press. All rights reserved.[SDGs]SDG3adenosine A2 receptor; cyclic AMP; hydroxymethylglutaryl coenzyme A reductase kinase; hydroxymethylglutaryl coenzyme A reductase kinase alpha 1; reactive oxygen metabolite; short hairpin RNA; TAR DNA binding protein; unclassified drug; AMPK alpha1 subunit, mouse; DNA binding protein; hydroxymethylglutaryl coenzyme A reductase kinase; PRKAA1 protein, human; TDP-43 protein, human; TDP-43 protein, mouse; adult; aged; amyotrophic lateral sclerosis; animal experiment; animal model; Article; cell function; clinical article; clinical feature; controlled study; cytoplasm; disease association; disease course; down regulation; enzyme activation; enzyme active site; enzyme activity; female; gene expression; gene location; gene repression; human; male; middle aged; motoneuron; nonhuman; nuclear localization signal; priority journal; protein localization; signal transduction; spinal cord; transgenic mouse; amyotrophic lateral sclerosis; animal; cell line; cell nucleus; disease model; gene expression regulation; metabolism; mouse; Mus musculus; Adult; Aged; AMP-Activated Protein Kinases; Amyotrophic Lateral Sclerosis; Animals; Cell Line; Cell Nucleus; Cytoplasm; Disease Models, Animal; DNA-Binding Proteins; Female; Gene Expression Regulation; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Motor Neurons; Spinal Cordjournal article10.1093/hmg/ddu497WOS:000350137900015