title: Activation of AMP-activated protein kinase α1 mediates mislocalization of TDP-43 in amyotrophic lateral sclerosis.
abstract: TAR 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.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Tz-Chuen
authors.initials: TC
authors.lastname: Ju
authors.affiliation: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Chen
authors.affiliation: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Yu-Sung
authors.initials: YS
authors.lastname: Jang
authors.affiliation: Institute of Neuroscience, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Lee
authors.affiliation: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hsing-Lin
authors.initials: HL
authors.lastname: Lai
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei 106, Taiwan and.
authors.forename: Hua-Chia
authors.initials: HC
authors.lastname: Tai
authors.affiliation: Department of Chemistry, National Taiwan University, Taipei 106, Taiwan and.
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
authors.affiliation: National Research Institute of Chinese Medicine, Taipei 112, Taiwan.
authors.forename: Yun-Lian
authors.initials: YL
authors.lastname: Lin
authors.affiliation: Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan bmychern@ibms.sinica.edu.tw btu@ibms.sinica.edu.tw.
authors.forename: Pang-Hsien
authors.initials: PH
authors.lastname: Tu
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan Division of Neuroscience, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan National Research Institute of Chinese Medicine, Taipei 112, Taiwan bmychern@ibms.sinica.edu.tw btu@ibms.sinica.edu.tw.
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D055372:AMP-Activated Protein Kinases; D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human; C578077:Tardbp protein, mouse; C548179:Prkaa1 protein, mouse; C526180:PRKAA1 protein, human