RT Journal Article SR Electronic T1 Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease JF Science Translational Medicine FD American Association for the Advancement of Science SP eaag0394 DO 10.1126/scitranslmed.aag0394 VO 9 IS 403 A1 Le Pichon, Claire E. A1 Meilandt, William J. A1 Dominguez, Sara A1 Solanoy, Hilda A1 Lin, Han A1 Ngu, Hai A1 Gogineni, Alvin A1 Sengupta Ghosh, Arundhati A1 Jiang, Zhiyu A1 Lee, Seung-Hye A1 Maloney, Janice A1 Gandham, Vineela D. A1 Pozniak, Christine D. A1 Wang, Bei A1 Lee, Sebum A1 Siu, Michael A1 Patel, Snahel A1 Modrusan, Zora A1 Liu, Xingrong A1 Rudhard, York A1 Baca, Miriam A1 Gustafson, Amy A1 Kaminker, Josh A1 Carano, Richard A. D. A1 Huang, Eric J. A1 Foreman, Oded A1 Weimer, Robby A1 Scearce-Levie, Kimberly A1 Lewcock, Joseph W. YR 2017 UL http://stm.sciencemag.org/content/9/403/eaag0394.abstract AB The genetics, pathology, and clinical manifestations of chronic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), are heterogeneous, which has made the development and testing of candidate therapeutics difficult. Here, Le Pichon et al. identify dual leucine zipper kinase (DLK) as a common regulator of neuronal degeneration in mouse models of ALS and Alzheimer’s disease and in human patient postmortem brain tissue. Deletion of DLK or treatment with a DLK inhibitor resulted in neuronal protection and slowing of disease progression after diverse insults in several mouse models of neurodegenerative disease. This suggests that DLK may have broad applicability as a therapeutic target for the treatment of a number of neurodegenerative diseases.Hallmarks of chronic neurodegenerative disease include progressive synaptic loss and neuronal cell death, yet the cellular pathways that underlie these processes remain largely undefined. We provide evidence that dual leucine zipper kinase (DLK) is an essential regulator of the progressive neurodegeneration that occurs in amyotrophic lateral sclerosis and Alzheimer’s disease. We demonstrate that DLK/c-Jun N-terminal kinase signaling was increased in mouse models and human patients with these disorders and that genetic deletion of DLK protected against axon degeneration, neuronal loss, and functional decline in vivo. Furthermore, pharmacological inhibition of DLK activity was sufficient to attenuate the neuronal stress response and to provide functional benefit even in the presence of ongoing disease. These findings demonstrate that pathological activation of DLK is a conserved mechanism that regulates neurodegeneration and suggest that DLK inhibition may be a potential approach to treat multiple neurodegenerative diseases.