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

2013; Rockefeller University Press; Volume: 210; Issue: 12 Linguagem: Inglês

10.1084/jem.20122832

1540-9538

Christine D. Pozniak, Arundhati Sengupta Ghosh, Alvin Gogineni, Jesse E. Hanson, Seung-Hye Lee, Jessica L. Larson, Hilda Solanoy, Daisy Bustos, Hong Li, Hai Ngu, Adrian M. Jubb, Gai Ayalon, Jian Wu, Kimberly Scearce‐Levie, Qiang Zhou, Robby M. Weimer, Donald S. Kirkpatrick, Joseph W. Lewcock,

Signaling Pathways in Disease

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.