| First Author | Liu YJ | Year | 2015 |
| Journal | Hum Mol Genet | Volume | 24 |
| Issue | 3 | Pages | 787-801 |
| PubMed ID | 25256353 | Mgi Jnum | J:318262 |
| Mgi Id | MGI:6858967 | Doi | 10.1093/hmg/ddu497 |
| Citation | Liu YJ, et al. (2015) Activation of AMP-activated protein kinase alpha1 mediates mislocalization of TDP-43 in amyotrophic lateral sclerosis. Hum Mol Genet 24(3):787-801 |
| abstractText | 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-alpha1 or exogenous expression of a dominant-negative AMPK-alpha1 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-alpha1 plays a critical role in TDP-43 mislocalization and the development of ALS; thus, AMPK-alpha1 may be a potential drug target for this devastating disease. |
