title: Dual leucine zipper kinase is required for excitotoxicity-induced neuronal degeneration.
abstract: 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.
authors.affiliation: 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.
authors.forename: Christine D
authors.initials: CD
authors.lastname: Pozniak
authors.forename: Arundhati
authors.initials: A
authors.lastname: Sengupta Ghosh
authors.forename: Alvin
authors.initials: A
authors.lastname: Gogineni
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Hanson
authors.forename: Seung-Hye
authors.initials: SH
authors.lastname: Lee
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Larson
authors.forename: Hilda
authors.initials: H
authors.lastname: Solanoy
authors.forename: Daisy
authors.initials: D
authors.lastname: Bustos
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Hai
authors.initials: H
authors.lastname: Ngu
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Jubb
authors.forename: Gai
authors.initials: G
authors.lastname: Ayalon
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Wu
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
authors.forename: Robby M
authors.initials: RM
authors.lastname: Weimer
authors.forename: Donald S
authors.initials: DS
authors.lastname: Kirkpatrick
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lewcock
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D000076122:Disks Large Homolog 4 Protein; D018698:Glutamic Acid / Q000502:physiology; D051528:Guanylate Kinases / Q000502:physiology; D007608:Kainic Acid / Q000633:toxicity; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000502:physiology; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000502:physiology; D013569:Synapses / Q000502:physiology
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C033652:postsynaptic density proteins; D018698:Glutamic Acid; D016202:N-Methylaspartate; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12; D051528:Guanylate Kinases; D007608:Kainic Acid