| First Author | Pozniak CD | Year | 2013 |
| Journal | J Exp Med | Volume | 210 |
| Issue | 12 | Pages | 2553-67 |
| PubMed ID | 24166713 | Mgi Jnum | J:207720 |
| Mgi Id | MGI:5559417 | Doi | 10.1084/jem.20122832 |
| Citation | Pozniak CD, et al. (2013) Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration. J Exp Med 210(12):2553-67 |
| abstractText | 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. |
