Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 4, 2024

Abstract Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant neurons, we identify a neuroprotective compound show that MAP4Ks may serve as therapeutic targets treating ALS. The lead broadly improves survival function of neurons directly converted from ALS patients. Mechanistically, it works inhibitor MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, normalizes subcellular distribution RANGAP1 TDP-43. Finally, mouse model inhibiting preserves significantly extends animal lifespan.

Language: Английский

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

Annual Review of Cell and Developmental Biology, Journal Year: 2019, Volume and Issue: 35(1), P. 501 - 521

Published: Oct. 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.

Language: Английский

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TNIK depletion induces inflammation and apoptosis in injured renal proximal tubule epithelial cells

AJP Renal Physiology, Journal Year: 2024, Volume and Issue: 326(5), P. F827 - F838

Published: March 14, 2024

In the aftermath of acute kidney injury (AKI), surviving proximal tubule epithelia repopulate injured tubules to promote repair. However, a portion cells fail repair [termed failed-repair (FR-PTCs)] and exert ongoing proinflammatory profibrotic effects. To better understand molecular drivers FR-PTC state, we reanalyzed mouse ischemia-reperfusion single-nucleus RNA-sequencing (snRNA-seq) atlas identify Traf2 Nck interacting kinase (

Language: 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, Journal Year: 2020, Volume and Issue: 117(52), P. 33597 - 33607

Published: Dec. 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.

Language: Английский

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Priming of NLRP3 inflammasome activation by Msn kinase MINK1 in macrophages

Cellular and Molecular Immunology, Journal Year: 2021, Volume and Issue: 18(10), P. 2372 - 2382

Published: Sept. 3, 2021

Language: Английский

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