Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury
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 per...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-11-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13024-019-0345-1 |
| _version_ | 1819068944247422976 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Derek S. Welsbie |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T16:42:11Z |
| format | Article |
| id | doaj.art-514b71f5220a494fa1e744e64eb61a2e |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-21T16:42:11Z |
| publishDate | 2019-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-514b71f5220a494fa1e744e64eb61a2e2022-12-21T18:57:05ZengBMCMolecular Neurodegeneration1750-13262019-11-0114111810.1186/s13024-019-0345-1Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injuryDerek S. Welsbie0Nikolaos K. Ziogas1Leyan Xu2Byung-Jin Kim3Yusong Ge4Amit K. Patel5Jiwon Ryu6Mohamed Lehar7Athanasios S. Alexandris8Nicholas Stewart9Donald J. Zack10Vassilis E. Koliatsos11Department of Ophthalmology, University of California, San DiegoDivision of Neuropathology, Department of Pathology, The Johns Hopkins University School of MedicineDivision of Neuropathology, Department of Pathology, The Johns Hopkins University School of MedicineDepartment of Ophthalmology, The Johns Hopkins University School of MedicineDivision of Neuropathology, Department of Pathology, The Johns Hopkins University School of MedicineDepartment of Ophthalmology, University of California, San DiegoDivision of Neuropathology, Department of Pathology, The Johns Hopkins University School of MedicineDepartment of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of MedicineDivision of Neuropathology, Department of Pathology, The Johns Hopkins University School of MedicineDivision of Neuropathology, Department of Pathology, The Johns Hopkins University School of MedicineDepartment of Ophthalmology, The Johns Hopkins University School of MedicineDepartment of Neurology, The Johns Hopkins University School of MedicineAbstract 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.http://link.springer.com/article/10.1186/s13024-019-0345-1Traumatic axonal injuryConcussionCell deathTraumatic brain injuryOptic neuropathyDual leucine zipper kinase |
| spellingShingle | 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 Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury Molecular Neurodegeneration Traumatic axonal injury Concussion Cell death Traumatic brain injury Optic neuropathy Dual leucine zipper kinase |
| title | Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury |
| title_full | Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury |
| title_fullStr | Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury |
| title_full_unstemmed | Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury |
| title_short | Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury |
| title_sort | targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury |
| topic | Traumatic axonal injury Concussion Cell death Traumatic brain injury Optic neuropathy Dual leucine zipper kinase |
| url | http://link.springer.com/article/10.1186/s13024-019-0345-1 |
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