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.