Novel inhibitors of acute, axonal DLK palmitoylation are neuroprotective and avoid the deleterious side effects of cell-wide DLK inhibition

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Апрель 24, 2024

Abstract Dual leucine-zipper kinase (DLK) drives acute and chronic forms of neurodegeneration, suggesting that inhibiting DLK signaling could ameliorate diverse neuropathological conditions. However, direct inhibition DLK’s domain in human patients conditional knockout mice both cause unintended side effects, including elevated plasma neurofilament levels, indicative neuronal cytoskeletal disruption. Indeed, we found a inhibitor acutely disrupted the axonal cytoskeleton caused vesicle aggregation cultured dorsal root ganglion (DRG) neurons, further cautioning against this therapeutic strategy. In seeking more precise intervention, retrograde (axon-to-soma) pro-degenerative requires acute, palmitoylation hypothesized modulating post-translational modification might be specifically neuroprotective than cell-wide inhibition. To address possibility, screened >28,000 compounds using high-content imaging assay quantitatively evaluates palmitoylation-dependent subcellular localization. Of 33 hits significantly altered localization non-neuronal cells, several reduced protected DRG neurons from DLK-dependent neurodegeneration. Mechanistically, two most selectively prevent stimulus-dependent pools DLK, process crucial for recruitment to vesicles. contrast, these minimally impact healthy avoid disruption associated with Importantly, our hit also reduce vivo, novel

Язык: Английский

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Multitasking: Dual Leucine Zipper–Bearing Kinases in Neuronal Development and Stress Management

Annual Review of Cell and Developmental Biology, Год журнала: 2019, Номер 35(1), С. 501 - 521

Опубликована: Окт. 6, 2019

The dual leucine zipper–bearing kinase (DLK) and (LZK) are evolutionarily conserved MAPKKKs of the mixed-lineage family. Acting upstream stress-responsive JNK p38 MAP kinases, DLK LZK have emerged as central players in neuronal responses to a variety acute traumatic injuries. Recent studies also implicate their function astrocytes, microglia, other nonneuronal cells, reflecting expanding roles multicellular response injury disease. Of particular note is potential link these kinases neurodegenerative diseases cancer. It thus critical understand physiological contexts under which activated, well signal transduction mechanisms that mediate specific functional outcomes. In this review we first provide historical overview biochemical dissection kinases. We then discuss recent findings on regulating activity enhance cellular protection following disease, focusing but not limited nervous system.

Язык: Английский

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Inhibition of GCK-IV kinases dissociates cell death and axon regeneration in CNS neurons

Proceedings of the National Academy of Sciences, Год журнала: 2020, Номер 117(52), С. 33597 - 33607

Опубликована: Дек. 14, 2020

Axon injury is a hallmark of many neurodegenerative diseases, often resulting in neuronal cell death and functional impairment. Dual leucine zipper kinase (DLK) has emerged as key mediator this process. However, while DLK inhibition robustly protective wide range disease models, it also inhibits axonal regeneration. Indeed, there are no genetic perturbations that known to both improve long-term survival promote To identify such neuroprotective target, we conducted set complementary high-throughput screens using protein inhibitor library human stem cell-derived retinal ganglion cells (hRGCs). Overlapping compounds promoted neuroprotection neurite outgrowth were bioinformatically deconvoluted specific kinases regulated axon This work identified the role germinal four (GCK-IV) additionally revealed their unexpected activity suppressing Using an adeno-associated virus (AAV) approach, coupled with genome editing, validated GCK-IV knockout improves survival, comparable knockout, simultaneously promoting Finally, found prevented attrition RGCs developing organoid cultures without compromising outgrowth, addressing major issue field retinas. Together, these results demonstrate for dissociating neurons druggability provides therapeutic options diseases.

Язык: Английский

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MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3

Oncogene, Год журнала: 2021, Номер 40(43), С. 6153 - 6165

Опубликована: Сен. 13, 2021

MAP4K4 is a Ste20 member and reported to play important roles in various pathologies, including cancer. However, the mechanism by which promotes pancreatic cancer not fully understood. It suggested that might function as promoter via specific downstream target(s) an organ-specific manner. Here we identified MLK3 direct target of MAP4K4. The associates with each other, phosphorylates on Thr738 increases kinase activity signaling. phosphorylation cell proliferation, migration, colony formation. Moreover, overexpressed human tumors directly correlates disease progression. MAP4K4-specific pharmacological inhibitor, GNE-495, impedes growth, induces death, arrests cycle Additionally, GNE-495 reduced tumor burden extended survival KPC mice inhibitor also protein expression, stroma, induced death murine tumors. These findings collectively suggest cancer, therefore therapies targeting alleviate patients.

Язык: Английский

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Priming of NLRP3 inflammasome activation by Msn kinase MINK1 in macrophages

Cellular and Molecular Immunology, Год журнала: 2021, Номер 18(10), С. 2372 - 2382

Опубликована: Сен. 3, 2021

Язык: Английский

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