Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury
| Autor: | Amit K Patel, Donald J. Zack, Yusong Ge, Jiwon Ryu, Byung Jin Kim, Derek S. Welsbie, Vassilis E. Koliatsos, Leyan Xu, Mohamed Lehar, Nikolaos K. Ziogas, Nicholas Stewart, Athanasios S. Alexandris |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Retinal Ganglion Cells Male Traumatic medicine.medical_treatment Concussion lcsh:Geriatrics Optic neuropathy Inbred C57BL lcsh:RC346-429 Traumatic axonal injury Mice 0302 clinical medicine Traumatic brain injury Injury - Trauma - (Head and Spine) Brain Injuries Traumatic 2.1 Biological and endogenous factors Retinal ganglion cell Aetiology Axon Neurons Kinase Neurodegeneration Protein kinase inhibitor MAP Kinase Kinase Kinases Cell biology Dual leucine zipper kinase medicine.anatomical_structure Neurological Axotomy DLK Research Article Cell death Leucine zipper medicine.drug_class Cell Survival MAP Kinase Signaling System Clinical Sciences Biology Retinal ganglion Neuroprotection 03 medical and health sciences Cellular and Molecular Neuroscience medicine Genetics Animals Molecular Biology Protein Kinase Inhibitors lcsh:Neurology. Diseases of the nervous system Leucine Zippers Neurology & Neurosurgery Animal Neurosciences medicine.disease Brain Disorders Mice Inbred C57BL LZK Disease Models Animal lcsh:RC952-954.6 030104 developmental biology Brain Injuries Disease Models Injury (total) Accidents/Adverse Effects Neurology (clinical) Injury - Traumatic brain injury 030217 neurology & neurosurgery |
| Zdroj: | Molecular neurodegeneration, vol 14, iss 1 Molecular Neurodegeneration, Vol 14, Iss 1, Pp 1-18 (2019) Molecular Neurodegeneration |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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