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J Exp Med. 2013 Nov 18;210(12):2553-67. doi: 10.1084/jem.20122832. Epub 2013 Oct 28.

Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration.

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Department of Neuroscience, 2 Department of Biomedical Imaging, 3 Department of Bioinformatics and Computational Biology, 4 Department of Protein Chemistry, 5 Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.


Excessive glutamate signaling is thought to underlie neurodegeneration in multiple contexts, yet the pro-degenerative signaling pathways downstream of glutamate receptor activation are not well defined. We show that dual leucine zipper kinase (DLK) is essential for excitotoxicity-induced degeneration of neurons in vivo. In mature neurons, DLK is present in the synapse and interacts with multiple known postsynaptic density proteins including the scaffolding protein PSD-95. To examine DLK function in the adult, DLK-inducible knockout mice were generated through Tamoxifen-induced activation of Cre-ERT in mice containing a floxed DLK allele, which circumvents the neonatal lethality associated with germline deletion. DLK-inducible knockouts displayed a modest increase in basal synaptic transmission but had an attenuation of the JNK/c-Jun stress response pathway activation and significantly reduced neuronal degeneration after kainic acid-induced seizures. Together, these data demonstrate that DLK is a critical upstream regulator of JNK-mediated neurodegeneration downstream of glutamate receptor hyper-activation and represents an attractive target for the treatment of indications where excitotoxicity is a primary driver of neuronal loss.

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