Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA217334 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Apoptotic neuron death is a common feature of many neurodegenerative diseases. Perhaps surprisingly, the exact mechanisms by which neurons undergo apoptosis have yet to be elucidated. We conducted an unbiased whole genome screen in human neurons to discover genes required for apoptotic neuron death, and found ATF2, MAP3K12 and JUN among top hits. We demonstrate that ATF2 is a previously unappreciated master regulator of neuron death. ATF2 is phosphorylated downstream of MAP3K12 (dual leucine zipper kinase) and MAP3K13 (leucine zipper kinase) and its phosphorylation is essential for transcriptional upregulation of JUN. We show that JUN upregulation is essential for apoptosis – but not its phosphorylation. Contrary to previous assumptions, cJun phosphorylation is therefore simply a correlate of JUN upregulation. In this study, we identify phosphorylation of ATF2 as a key event in the mechanism of neuronal apoptosis, linking the MAP3K12/13 kinase cascade to transcriptional upregulation of JUN. Since targeting members of this signaling pathway to block neuronal death has proved difficult, ATF2 offers a novel and promising alternative.
2025-04-30 | GSE282354 | GEO
Project description:Mitogen-activated protein kinases (MAPKs) drive key signaling cascades during neuronal survival and degeneration. The re-localization of kinases to specific subcellular compartments is a critical mechanism to locally control signaling activity and specificity upon stimulation. However, how MAPK signaling components tightly control their localization remains largely unknown. Here, we systematically analyzed the phosphorylation and membrane localization of all MAPKs expressed in dorsal root ganglia neurons, under control and stress conditions. We found that MAP3K12/ dual leucine zipper kinase (DLK) is the only MAPK that becomes phosphorylated and palmitoylated, and it is recruited to sphingomyelin rich vesicles upon stress. The DLK stress-induced vesicle assembly is essential for kinase activation; blocking DLK-membrane interactions inhibits downstream signaling, while DLK recruitment to ectopic subcellular structures is sufficient to induce kinase activation. We show that the localization of DLK to newly formed vesicles is essential for local signaling and inhibition of membrane internalization blocks DLK activation and protects against neurodegeneration. These data establish vesicular assemblies as dynamically regulated platforms for DLK signaling during neuronal stress responses.
| MSV000088168 | MassIVE
Project description:Alzheimer’s disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. To model AD-relevant neurodegeneration driven by tau, we overexpressed non-mutated human tau in primary mouse neurons and observed substantial axonal degeneration and cell death, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau-expressing neurons. Gene profiling analysis further revealed significant alterations in the mitogen-activated protein kinase (MAPK) pathway; moreover, inhibitors of dual leucine zipper kinase (DLK) and c-Jun N-terminal kinase (JNK) were effective in alleviating wild-type human tau-induced neurodegeneration. In contrast, mutant P301L human tau was less toxic to neurons, despite causing comparable DNA damage. Axonal DLK activation induced by wild-type tau potentiated the impact of DNA damage response, resulting in overt neurotoxicity. In summary, we have established a cellular tauopathy model highly relevant to AD and identified a functional synergy between the MAPK-DLK axis and DNA damage response in the neuronal degenerative process.
2023-11-15 | GSE246259 | GEO
Project description:Dual Leucine-zipper Kinase (DLK)-dependent stress signaling is a critical determinant of neuronal survival and regenerative potential following axon damage, but it remains uncertain whether injury-activated DLK is adequate to initiate and maintain a pro-regenerative transcriptional response in the CNS. Using a drug-activatable DLK construct, we stimulated stress signaling for comparison of the retinal transcriptional response to, and in addition to, the response stimulated by mouse optic nerve injury in wildtype mice and in the context of partial axon regeneration enabled by disruption of the tumor suppressor PTEN.
2024-09-29 | GSE278304 | GEO
Project description:The Cytoskeletal Stress Response Pathway: a homeostatic system driven by Dual Leucine Zipper Kinase (DLK)
| PRJNA1025272 | ENA
Project description:Most transcription factors possess at least one long intrinsically disordered transactivation domain that binds to a variety of co-activators and co-repressors and plays a key role in modulating the transcriptional activity. Despite the crucial importance of these mechanisms, the structural and functional basis of transactivation domain in yet poorly understood. Here, we focused on ATF4/CREB-2, an essential transcription factor for cellular stress adaptation. We found that the N-terminal region of the transactivation domain is involved in transient long-range interactions with the basic-leucine zipper domain. In vitro phosphorylation assays with the protein kinase CK2 show that the presence of the basic-leucine zipper domain is required for optimal phosphorylation of the transactivation domain. This study uncovers the intricate coupling existing between the transactivation and basic-leucine zipper domains of ATF4 and highlights its potential functional relevance.
2023-03-11 | PXD029704 | Pride
Project description:Traumatic brain injury (TBI) is a risk factor for neurodegeneration, however little is known about how different neuron types respond to this kind of injury. In this study, we follow neuronal populations over several months after a single mild TBI (mTBI) to assess long ranging consequences of injury at the level of single, transcriptionally defined neuronal classes. We find that the stress responsive Activating Transcription Factor 3 (ATF3) defines a population of cortical neurons after mTBI. We show that neurons that activate ATF3 upregulate stress-related genes while repressing many genes, including commonly used markers for these cell types. Using an inducible reporter linked to ATF3, we genetically mark damaged cells to track them over time. Notably, we find that a population in layer V undergoes cell death acutely after injury, while another in layer II/III survives long term and retains the ability to fire action potentials. To investigate the mechanism controlling layer V neuron death, we genetically silenced candidate stress response pathways. We found that the axon injury responsive kinase MAP3K12, also known as dual leucine zipper kinase (DLK), is required for the layer V neuron death. This work provides a rationale for targeting the DLK signaling pathway as a therapeutic intervention for traumatic brain injury. Beyond this, our novel approach to track neurons after a mild, subclinical injury can inform our understanding of neuronal susceptibility to repeated impacts.
2025-01-13 | GSE262317 | GEO
Project description:A mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) was applied to analyze 16 patient-derived xenografts (PDXs) leading to the discovery that Death-Associated Protein Kinase 3 (DAPK3) is significantly and specifically overexpressed in triple negative breast cancer (TNBC). Validation studies confirmed the enrichment of DAPK3 at the protein level, independent of RNA expression, in both TNBC cell lines and tumors. Genomic knockout of DAPK3 in TNBC cell lines inhibited in vitro migration and invasion, along with downregulation of an epithelial-mesenchymal transition (EMT) signature. The kinase and leucine-zipper domains within DAPK3 were shown by mutational analysis to be essential for functionality. Notably, DAPK3 was found to inhibit the levels of desmoplakin (DSP), a crucial component of the desmosome complex, thereby explaining TNBC migration and invasion effects. Further exploration with immunoprecipitation-mass spectrometry (IP-MS) identified Leucine-zipper protein 1 (LUZP1) as a strong binding partner of DAPK3, engaging in a leucine-zipper-domain-mediated interaction that protects DAPK3 from degradation. Thus, DAPK3 emerges as a novel regulator of EMT components in TNBC.
2025-05-06 | PXD049187 | Pride
Project description:Injury to peripheral axons initiates a complex cascade of cellular responses, including cytoskeletal disassembly, axon transport disruption, and ultimately axon regeneration. Central to this process is the MAP triple kinase Dual-Leucine Zipper Kinase (DLK), activated by injury and other neuronal stressors. Here, we propose the existence of a homeostatic mechanism termed the Cytoskeletal Perturbation Response (CPR). We investigate this hypothesis by examining the response of cultured dorsal root ganglion (DRG) neurons to low dose nocodazole treatment, a cytoskeletal perturbing agent. To gain insights into DLK-dependent transcriptional changes following cytoskeletal insult, we performed bulk RNA sequencing on cultured neurons treated for 16 hours. Using a fully crossed two-factor design, we determined the interactive effect of DLK on nocodazole- dependent transcriptional changes. Our study demonstrates that cytoskeletal perturbation triggers DLK-dependent signaling cascades, leading to significant transcriptional changes. These changes involve transcription factors (Jun, Egr1, Atf3) and MAP kinase regulators (DUSPs), pointing to a regulatory network that attenuates DLK signaling. Taken together, our findings suggest that cytoskeletal perturbation activates a DLK-dependent homeostatic mechanism, the CPR, which orchestrates transcriptional changes and morphological adaptations to repair neuronal damage. The CPR bears similarities to established homeostatic responses, offering insights into the intricate processes that underlie axon regeneration and cellular repair.
2023-10-11 | GSE244883 | GEO
Project description:Excitotoxicity is a primary pathological process directing neuronal cell death in both acute neurological disorders and neurodegenerative diseases such as ischemic stroke and Alzheimer’s disease. We use mouse cultured cortical neuron treated with 100uM of Glutamate for a model of excitotoxicity and applied N-terminomics (TAILS) method to identify the neuronal proteins aberrantly modified in excitotoxicity
2023-04-07 | PXD040648 | Pride