Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury

Derek S. Welsbie, Nikolaos K. Ziogas, Leyan Xu, Byung Jin Kim, Yusong Ge, Amit K. Patel, Jiwon Ryu, Mohamed Lehar, Athanasios S. Alexandris, Nicholas Stewart, Donald J. Zack, Vassilis E. Koliatsos

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number44
JournalMolecular neurodegeneration
Volume14
Issue number1
DOIs
StatePublished - Nov 27 2019

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Leucine Zippers
Phosphotransferases
Retinal Ganglion Cells
Traumatic Brain Injury
Diffuse Brain Injury
Wounds and Injuries
Axotomy
Cell Death

Keywords

  • Cell death
  • Concussion
  • DLK
  • Dual leucine zipper kinase
  • LZK
  • Optic neuropathy
  • Retinal ganglion cell
  • Traumatic axonal injury
  • Traumatic brain injury

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury. / Welsbie, Derek S.; Ziogas, Nikolaos K.; Xu, Leyan; Kim, Byung Jin; Ge, Yusong; Patel, Amit K.; Ryu, Jiwon; Lehar, Mohamed; Alexandris, Athanasios S.; Stewart, Nicholas; Zack, Donald J.; Koliatsos, Vassilis E.

In: Molecular neurodegeneration, Vol. 14, No. 1, 44, 27.11.2019.

Research output: Contribution to journalArticle

Welsbie, DS, Ziogas, NK, Xu, L, Kim, BJ, Ge, Y, Patel, AK, Ryu, J, Lehar, M, Alexandris, AS, Stewart, N, Zack, DJ & Koliatsos, VE 2019, 'Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury', Molecular neurodegeneration, vol. 14, no. 1, 44. https://doi.org/10.1186/s13024-019-0345-1
Welsbie, Derek S. ; Ziogas, Nikolaos K. ; Xu, Leyan ; Kim, Byung Jin ; Ge, Yusong ; Patel, Amit K. ; Ryu, Jiwon ; Lehar, Mohamed ; Alexandris, Athanasios S. ; Stewart, Nicholas ; Zack, Donald J. ; Koliatsos, Vassilis E. / Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury. In: Molecular neurodegeneration. 2019 ; Vol. 14, No. 1.
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AU - Xu, Leyan

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AU - Ge, Yusong

AU - Patel, Amit K.

AU - Ryu, Jiwon

AU - Lehar, Mohamed

AU - Alexandris, Athanasios S.

AU - Stewart, Nicholas

AU - Zack, Donald J.

AU - Koliatsos, Vassilis E.

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