Altered nuclear envelope homeostasis is a key pathogenic event in C9ORF72-linked ALS/FTD

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 4, 2024

SUMMARY ALS and FTD are complex neurodegenerative disorders that primarily affects motor neurons in the brain spinal cord, cortical frontal lobe. Although pathogenesis of ALS/FTD is unclear, recent research spotlights nucleocytoplasmic transport impairment, DNA damage, nuclear abnormalities as drivers neuronal death. In this study, we show loss envelope (NE) integrity a key pathology associated with pore (NPC) injury C9ORF72 mutant neurons. Importantly, mechanical stresses generated by cytoskeletal forces on NE can lead to NPC injury, integrity, accumulation damage. demonstrate restoring tensional homeostasis, disconnecting nucleus from cytoskeleton, rescue reduce damage cells. Together, our data suggest modulation homeostasis repair may represent novel promising therapeutic target for ALS/FTD.

Language: Английский

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Nesprin proteins: bridging nuclear envelope dynamics to muscular dysfunction

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: April 2, 2024

Abstract This review presents a comprehensive exploration of the pivotal role played by Linker Nucleoskeleton and Cytoskeleton (LINC) complex, with particular focus on Nesprin proteins, in cellular mechanics pathogenesis muscular diseases. Distinguishing itself from prior works, analysis delves deeply into intricate interplay LINC emphasizing its indispensable contribution to maintaining structural integrity, especially mechanically sensitive tissues such as cardiac striated muscles. Additionally, significant association between mutations proteins onset Dilated Cardiomyopathy (DCM) Emery-Dreifuss Muscular Dystrophy (EDMD) is highlighted, underscoring their disease pathogenesis. Through examination DCM EDMD cases, elucidates disruptions nuclear morphology alterations, developmental disorders, thus essential function an intact complex preserving muscle physiological functions. Moreover, provides novel insights implications for dynamics diseases, particularly functional integrity. Furthermore, advanced therapeutic strategies, including rectifying gene mutations, controlling protein expression, enhancing functionality, augmenting cell are proposed. By shedding light molecular mechanisms underlying nuclear-cytoskeletal interactions, lays groundwork future research interventions aimed at addressing genetic disorders.

Language: Английский

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Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(3), P. 686 - 699

Published: March 13, 2024

Abstract Cancer cells often exhibit resistance to apoptotic cell death, but they may be vulnerable other types of death. Elucidating additional mechanisms that govern cancer death is crucial for developing new therapies. Our research identified cyclic AMP-responsive element-binding protein 3 (CREB3) as a regulator and initiator unique mechanism known karyoptosis. This process characterized by nuclear shrinkage, deformation, the loss components following membrane rupture. We found N-terminal domain (aa 1-230) full-length CREB3 (CREB3-FL), which anchored inner (INM), interacts with lamins chromatin DNA. interaction maintains balance between outward force exerted tightly packed DNA inward constraining force, thereby preserving INM integrity. Under endoplasmic reticulum (ER) stress, aberrant cleavage CREB3-FL at leads abnormal accumulation cleaved form (CREB3-CF). disrupts attachment INM, resulting in sudden rupture onset Proteomic studies revealed CREB3-CF overexpression induces damage response akin caused UVB irradiation, associated cellular senescence cells. These findings demonstrated dysregulation key factor karyoptotic Consequently, these suggest therapeutic strategies treatment exploit

Language: Английский

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Transcriptional dynamics during Heliothis zea nudivirus 1 infection in an ovarian cell line from Helicoverpa zea

Journal of General Virology, Journal Year: 2025, Volume and Issue: 106(1)

Published: Jan. 13, 2025

Nudiviruses (family Nudiviridae) are double-stranded DNA viruses that infect various insects and crustaceans. Among them, Heliothis zea nudivirus 1 (HzNV-1) represents the rare case of a lepidopteran inducing sexual pathology. Studies about molecular pathological dynamics HzNV-1 or other nudiviruses scarce. Hence, this study aims to provide transcriptomic profile in an ovary-derived cell line Helicoverpa (HZ-AM1), during early (3, 6 9 h post-infection) advanced (12 24 stages infection. Total RNA was extracted from both virus- mock-infected cells, RNA-seq analysis performed examine virus host transcriptional dynamics. Hierarchical clustering used categorize viral genes, while differential gene expression utilized pinpoint genes significantly affected by classified 154 into four temporal phases, with phases mainly involving transcription replication later including for virion assembly. In addition, novel promoter motif identified upstream region early-expressed genes. Host revealed significant upregulation heat shock protein downregulation histone The identification patterns enhances understanding pathology, differentially expressed highlight key pathways most hijacked

Language: Английский

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RSK2 and its binding partners: an emerging signaling node in cancers

Archives of Pharmacal Research, Journal Year: 2025, Volume and Issue: unknown

Published: May 5, 2025

Language: Английский

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Evaluation of image analysis tools for the measurement of cellular morphology

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: May 15, 2025

Morphological cell analysis offers a means of identification and classification key morphological measurement parameters linked to bioactivity health and, as such, it is great interest academic industrial research sectors. Widespread adoption this approach has yet occur, partially due the lack alignment in methodologies output metrics, limiting data comparability. Work within metrology wider multidisciplinary community aims reduce variability through improved image acquisition methodologies. Furthermore, improve comparability, also focused on minimal set measurands, often termed critical quality attributes (CQAs), which are traceable standardised (SI) units measurement. Whilst efforts defining CQAs have progressed significantly for healthcare applications, there still numerous challenges associated with cultured cells due, part, their complex heterogenous nature. This review evaluates various automated tools developed four commonly considered features: nucleus, actin cytoskeleton, mitochondria, membrane. The outputs from each tool been evaluated coinciding highlighted potential CQAs.

Language: Английский

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RSK2-mediated cGAS phosphorylation induces cGAS chromatin-incorporation-mediated cell transformation and cancer cell colony growth

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Oct. 18, 2024

Abstract Cyclic guanosine-adenosine monophosphate synthase (cGAS) is a key cytosolic DNA sensor that plays pivotal role in the innate immune response. Although decade of research on cGAS has advanced our understanding inflammasome formation, cytokine production, and signaling pathways, nucleus remains unclear. In this study, we found nuclear localization endogenous stably expressed differed from transiently cGAS, which mainly localized cytosol. nucleus, tightly bound to chromatin DNA. The binding was dependent RSK2. Our molecular mechanism study indicated N-lobe RSK2 harboring 1–323 interacted with NTase domain residues 213–330. This interaction increased RSK2-induced phosphorylation at Ser120 Thr130, resulting chromatin. Importantly, epidermal growth factor (EGF)-induced cell transformation anchorage-independent colony showed an increase factors, such as EGF or bFGF, stable expression compared mock expression. Notably, cGAS-S120A/T130A mutant abolished increasing effect JB6 Cl41 cells SK-MEL-2 malignant melanoma cells. results suggested cGAS’s binding, indispensable RSK2-dependent Ser120/Thr130, provides first clue how may participate remodeling nucleus.

Language: Английский

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Unraveling the Ferroptosis-inducing Potential of Methanol Leaves Extract of Prosopis Juliflora Via Downregulation of SLC7A11 and GPX4 mRNA Expression in A549 Lung Cancer Cells

Current Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 32(7), P. 1442 - 1456

Published: Oct. 25, 2024

Introduction: Prosopis juliflora has been employed in many traditional treatments. As evidenced by our earlier research, leaf methanol extract (PJME) a promising future the fight against lung cancer. It may also be used conjunction with other treatments to effectively manage Aims and Objective: The main objective of this study was explore potential PJME inhibit cancer A549 cells, along its underlying mechanisms action. Methods: antiproliferative effects were determined using MTT LDH tests. Apoptosis- inducing capacity evaluated DAPI staining, caspase-3 test, cytochrome C assay, PARP cleavage, qRT-PCR. To investigate mechanism action cancer, levels ROS, MMP, GSH, MDA, specific ferroptosis indicators measured. Results: experimental data current indicated that exposure cells reduced cell viability increased cellular cytotoxicity. apoptosis-inducing ability validated enhanced nuclear condensation, level caspase- 3, C, release. In addition, qRT-PCR investigations verified administration led decrease expression anti-apoptotic gene Bcl2 while enhancing mRNA pro-apoptotic genes, such as Bax caspase-3, cells. Conclusion: found activate pathways, elevated reactive oxygen species (ROS) generation, changes antioxidant markers (MDA GSH), decreased SLC7A11 GPX4. results present clearly showed inhibited proliferation induced reducing important targets Further research is necessary fully understand clinical efficacy before it can investigated supplemental or adjuvant therapy for

Language: Английский

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Karyoptosis as a novel type of UVB-induced regulated cell death

Free Radical Research, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 15

Published: Dec. 3, 2024

Karyoptosis is a type of regulated cell death (RCD) characterized by explosive nuclear rupture caused loss membrane integrity, resulting in the release genomic DNA and other components into cytosol extracellular environment. The mechanism underlying karyoptosis involves delicate balance between following forces: expansion force exerted tightly packed nucleus, resistance provided lamina at inner (INM), tensile from cytoskeleton that helps position nucleus center cytoplasm, allowing it to remain maximally expanded. In addition, CREB3, II integral protein with DNA-binding ability, tethers chromatin INM, providing tightening through interactions prevent rupture. UVB radiation can trigger this process, inducing CREB3-FL cleavage producing CREB3-CF. Therefore, acts as an intrinsic factor induction karyoptosis. Importantly, biochemical analysis RCD markers shows distinct forms death, such apoptosis, autophagy, necroptosis, pyroptosis. This review explores mechanisms involved maintaining integrity role CREB3 triggering provides brief suggestions on potential implications for targeting cancer cells.

Language: Английский

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