Regulation of the Activity of the Dual Leucine Zipper Kinase by Distinct Mechanisms
Abstract
:1. (Patho)physiological Actions of DLK
Modeled Disease or Disease Mechanism | In Vivo/In Vitro Model (Organism) | Experimental Disease Model | Involvement of DLK | Ref |
---|---|---|---|---|
Seizure/excitotoxic neurodegeneration | Mouse | Kainic acid | Inducible DLK knock-out reduced neuronal degeneration. | [18] |
Amyotrophic lateral sclerosis (ALS) | Mouse | SOD1G93A mutation | Deletion of DLK preserved large myelinated axons and protected neurons in lumbar spinal cord. | [19] |
Mouse | SOD1G93A mutation | Dual inhibition of DLK and LZK suppressed elevation of p-c-Jun and neurofilament light (Nf-L). | [20] | |
Mouse Mouse primary neurons Human tissue (postmortem) | SOD1G93A TDP-43A315T Trophic factor deprivation ALS patients’ lumbar spinal cord | Deletion or inhibition of DLK reduced p-c-Jun; protected against axon degeneration, neuronal loss, and functional decline; and improved survival of SOD1G93A mice. p-JNK and p-c-Jun were elevated in patient lumbar spinal cord lysates. | [1] | |
Alzheimer’s disease (AD) | Mouse Human tissue (postmortem) | PS2APP TauP301L AD patients’ brain | Deletion of DLK reduced p-c-Jun in immunoblot and immunochemistry and improved preserved cognitive function. P-c-Jun was detected in dentate gyrus via immunohistochemistry. | [1] |
Human ESC-derived cortical neurons Mouse | ApoE2, ApoE3, ApoE4 treatment | ApoE increased DLK, while ApoE3 slowed DLK protein turnover rate. | [2] | |
Mouse primary hippocampal and cortical neurons | Overexpression of human tau | DLK inhibition reduced p-JNK and p-c-Jun and cytotoxicity | [6,21] | |
Mouse | APP/PS1 mouse model | Downregulation of DLK by MiR-191-5p inhibited Amyloid-beta-induced microglial cell injury. | [22] | |
Parkinson’s disease (PD) | Mouse | 6OHDA (neurotoxin) (intra-striatal) | AAV-directed expression of d/n-DLK (K152A) had anti-apoptotic and trophic effects on dopaminergic neurons. | [23] |
Mouse | MPTP (mitochondrial toxin) | DLK inhibition suppressed c-Jun phosphorylation in dopaminergic neurons of the substantia nigra. | [24] | |
Traumatic brain injury | Mouse | Impact acceleration | Injury activated the DLK-JNK axis in retinas, while DLK deletion blunted c-Jun-phosphorylation. | [25] |
Traumatic brain injury (subarachnoid hemorrhage) | Rat | Endovascular perforation | DLK silencing attenuated brain edema and neuronal apoptosis and improved neurobehavioral functions. DLK overexpression deteriorated neurobehavioral functions and brain edema. | [26] |
Rat | Endovascular perforation | Tozasertib reduced neuronal apoptosis, and p-JNK attenuated brain edema and improved neurobehavioral deficits. | [27] | |
Stroke/traumatic brain injury | Mouse | Photothrombosis-induced focal cortical stroke | Knockdown of post-stroke upregulated protein CCR5 inhibited DLK expression. | [28] |
Tested Inhi- bitor | Clinical Trial or Model Organism (In Vivo/In Vitro) | Experimental Disease Model | Modeled Disease or Disease Mechanism | Effect of DLK Inhibition | Ref |
---|---|---|---|---|---|
GNE-3511 | Mouse | Optic nerve crush MPTP (mitochondrial toxin) | Acute nerve injury Parkinson’s disease (PD) | Reduced c-Jun phosphorylation and neurodegeneration. | [24] |
D. melanogaster | dFmr1 deletion | Fragile-X-syndrome (FXS) | Suppressed defects in neuronal development and behavior. | [29] | |
Mouse | Sciatic nerve transection | Nerve injury/neuropathic pain | Reduced mechanical allodynia. | [30] | |
Mouse Mouse embryonal DRG explant culture | Cyclophosphamide treatment (p. o.) | Cyclophosphamide-induced cystitis, inflammation, pain, and bladder pathology | Reduced pain and c-Jun phosphorylation in DRG, suppressed histamine-release from mast cells, and neuronal activation in the spinal cord and bladder pathology. | [31] | |
Mouse embryonal DRG explant culture | Vincristine NGF withdrawal Axotomy/forskolin Axotomy | Wallerian axon degeneration | Delayed and reduced neurodegeneration. Reduced c-Jun-phosphorylation. | [32,33,34,35,36] | |
Mouse sympathetic neurons (with latent HSV infection) | Forskolin, IL-1beta and tetrodotoxin Forskolin + heat shock PI3K inhibition by LY204002 | HSV reactivation via neuronal hyperexcitation HSV reactivation by stress | Prevented HSV reactivation. | [37,38,39] | |
Mouse cortical and hippocampal neurons | Overexpression of human Tau | Alzheimer’s disease (AD) | Prevented phosphory-lation of JNK + c-Jun and reduced cytotoxicity. | [6] | |
Mouse | Deletion of Myelin Regulatory Factor (Myrf) (model of demyelination) | Multiple sclerosis (MS) | Blocked c-Jun-phosphorylation and apoptosis of chronically demyelinated neurons. | [40] | |
GNE-8505 | Mouse | SOD1G93A mutation | Amyotrophic lateral sclerosis (ALS) | Reduced p-c-Jun. | [1] |
CMT2 patient-derived iPSC motor neurons | Patient-derived cells in vitro | Charcot-Marie-Tooth neuropathy Type 2 (CMT2) | Reduced p-c-Jun and restored mitochondrial dysfunction. | [41] | |
IACS-52825 | Mouse | Cisplatin treatment (i.p.) | Chemotherapy-induced peripheral neuropathy (CIPN) | Reversed mechanical allodynia. | [42] |
IACS-8287 | Mouse | Cisplatin treatment (i.p.) | Chemotherapy-induced peripheral neuropathy (CIPN) Chemotherapy-induced cognitive impairment (CICI) | Prevented mechanical allodynia, loss of intra-epidermal nerve fibers, cognitive deficits, and impairments of brain connectivity. | [43] |
GDC-0134 | Human (Phase I clinical trial) | ALS patients | Amyotrophic lateral sclerosis (ALS) | Terminated due to adverse effects. | [4] |
DN-1289 | Mouse | Optic nerve crush SOD1G93A mutation | Acute nerve injury Amyotrophic lateral sclerosis (ALS) | Suppressed elevation of p-c-Jun. | [20] |
Sunitinib | Human ESC-derived RGCs | Colchicine 1 µM | Axonal injury | Increased dose-dependent survival. | [44] |
Mouse | Impact acceleration (model of TBI) | Traumatic brain injury (TBI) | Increased RGC survival. | [25] | |
Mouse Rat | Optic nerve crush | Glaucoma | Administration by eye drop improved RCG survival. | [45] | |
Tozasertib | Rat Mouse primary RGCs | Laser-induced ocular hypertension Optic nerve transection | Glaucoma, traumatic optic neuropathies | Increased survival of RGCs and reduced axon loss. Increased survival of RGCs | [7] |
Rat | Endovascular perforation | Brain injury after SAH | Reduced apoptosis of neurons. | [27] | |
Human ESC-derived RGCs | Colchicine 1 µM | Axonal injury | Increased dose-dependent survival. | [44] | |
Mouse primary RGCs | Colchicine 1 µM | Glaucoma | Increased survival of RGCs. | [46] |
2. Regulation of DLK
2.1. Regulation of DLK at the Transcriptional Level
2.2. Regulation of DLK at the Post-Transcriptional Level
2.3. Regulation of DLK at the Post-Translational Level
2.3.1. Phosphorylation of DLK
2.3.2. Dephosphorylation of DLK
2.3.3. Palmitoylation of DLK
2.3.4. Regulation via Protein–Protein Interactions
2.3.5. Regulation of DLK via Its Oligomerization
3. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Model Organism | Protein | Accession Number | Isoforms | Length |
---|---|---|---|---|
Homo sapiens | MAP3K12, ZPK | NP_001180440.1 | Isoform 1 | 892 aa |
Homo sapiens | MAP3K12, ZPK | NP_006292.3 | Isoform 2 | 859 aa |
Mus musculus | MAP3K12, DLK | NP_001157115.1 | (not described) | 888 aa |
Rattus norvegicus | MAP3K12, MUK | NP_037187.1 | (not described) | 888 aa |
Mesocricetus auratus | MAP3K12, DLK | XP_040609646.1 | Isoform X1 | 920 aa |
Mesocricetus auratus | MAP3K12, DLK | XP_012966775.1 | Isoform X2 | 862 aa |
Mesocricetus auratus | MAP3K12, DLK | XP_005067383.1 | Isoform X3 | 892 aa |
Caenorhabditis elegans | DLK-1 | NP_001021443.1 | long | 928 aa |
Caenorhabditis elegans | DLK-1 | NP_001021445.1 | short | 577 aa |
Drosophila melanogaster | Wallenda, WND | NP_649137.3 | Isoform (A) | 977 aa |
Drosophila melanogaster | Wallenda, WND | NP_788540.1 | Isoform (B) | 977 aa |
Drosophila melanogaster | Wallenda, WND | NP_788541.1 | Isoform (C) | 977 aa |
Drosophila melanogaster | Wallenda, WND | NP_001189132.1 | Isoform (D) | 950 aa |
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Köster, K.-A.; Dethlefs, M.; Duque Escobar, J.; Oetjen, E. Regulation of the Activity of the Dual Leucine Zipper Kinase by Distinct Mechanisms. Cells 2024, 13, 333. https://doi.org/10.3390/cells13040333
Köster K-A, Dethlefs M, Duque Escobar J, Oetjen E. Regulation of the Activity of the Dual Leucine Zipper Kinase by Distinct Mechanisms. Cells. 2024; 13(4):333. https://doi.org/10.3390/cells13040333
Chicago/Turabian StyleKöster, Kyra-Alexandra, Marten Dethlefs, Jorge Duque Escobar, and Elke Oetjen. 2024. "Regulation of the Activity of the Dual Leucine Zipper Kinase by Distinct Mechanisms" Cells 13, no. 4: 333. https://doi.org/10.3390/cells13040333