Research ArticleNeurodegenerative Disease

Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease

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Science Translational Medicine  16 Aug 2017:
Vol. 9, Issue 403, eaag0394
DOI: 10.1126/scitranslmed.aag0394

A new therapeutic target zips into view

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.

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