期刊
HUMAN MOLECULAR GENETICS
卷 24, 期 3, 页码 787-801出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddu497
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资金
- National Science Council [NSC 100-2325-B001-003, NSC 101-2325-B-001-003, NSC 102-2325-B-001-003, NSC 102-2321-B-001-068-MY3]
- Institute of Biomedical Sciences of Academia Sinica
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-alpha 1 or exogenous expression of a dominant-negative AMPK-alpha 1 mutant reduced TDP-43 mislocalization. Suppression of AMPK activity using cAMP-simulating agents rescued the mislocalization of TDP-43 in N5C34 cells and delayed disease progression in TDP-43 transgenic mice. Our findings demonstrate that activation of AMPK-alpha 1 plays a critical role in TDP-43 mislocalization and the development of ALS; thus, AMPK-alpha 1 may be a potential drug target for this devastating disease.
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