Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury.
BACKGROUND
Traumatic brain injury (TBI) is a major cause of CNS neurodegeneration and has no disease-altering therapies. It is commonly associated with a specific type of biomechanical disruption of the axon called traumatic axonal injury (TAI), which often leads to axonal and sometimes perikaryal degeneration of CNS neurons. We have previously used genome-scale, arrayed RNA interference-based screens in primary mouse retinal ganglion cells (RGCs) to identify a pair of related kinases, dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) that are key mediators of cell death in response to simple axotomy. Moreover, we showed that DLK and LZK are the major upstream triggers for JUN N-terminal kinase (JNK) signaling following total axonal transection. However, the degree to which DLK/LZK are involved in TAI/TBI is unknown.


METHODS
Here we used the impact acceleration (IA) model of diffuse TBI, which produces TAI in the visual system, and complementary genetic and pharmacologic approaches to disrupt DLK and LZK, and explored whether DLK and LZK play a role in RGC perikaryal and axonal degeneration in response to TAI.


RESULTS
Our findings show that the IA model activates DLK/JNK/JUN signaling but, in contrast to axotomy, many RGCs are able to recover from the injury and terminate the activation of the pathway. Moreover, while DLK disruption is sufficient to suppress JUN phosphorylation, combined DLK and LZK inhibition is required to prevent RGC cell death. Finally, we show that the FDA-approved protein kinase inhibitor, sunitinib, which has activity against DLK and LZK, is able to produce similar increases in RGC survival.


CONCLUSION
The mitogen-activated kinase kinase kinases (MAP3Ks), DLK and LZK, participate in cell death signaling of CNS neurons in response to TBI. Moreover, sustained pharmacologic inhibition of DLK is neuroprotective, an effect creating an opportunity to potentially translate these findings to patients with TBI.
['Welsbie|Derek S|DS|0000-0002-3772-9335', 'Ziogas|Nikolaos K|NK|', 'Xu|Leyan|L|', 'Kim|Byung-Jin|BJ|', 'Ge|Yusong|Y|', 'Patel|Amit K|AK|', 'Ryu|Jiwon|J|', 'Lehar|Mohamed|M|', 'Alexandris|Athanasios S|AS|', 'Stewart|Nicholas|N|', 'Zack|Donald J|DJ|', 'Koliatsos|Vassilis E|VE|']
D000818:Animals D000070642:Brain Injuries, Traumatic D002470:Cell Survival D004195:Disease Models, Animal D016350:Leucine Zippers D020930:MAP Kinase Kinase Kinases D020935:MAP Kinase Signaling System D008297:Male D008810:Mice, Inbred C57BL D009474:Neurons D047428:Protein Kinase Inhibitors D012165:Retinal Ganglion Cells
Dual leucine zipper kinase Traumatic brain injury Traumatic axonal injury Retinal ganglion cell DLK LZK Cell death Concussion Optic neuropathy