Phase behavior and dissociation kinetics of lamins in a polymer model of progeria

The Journal of Chemical Physics, Год журнала: 2025, Номер 162(18)

Опубликована: Май 8, 2025

One of the key structural proteins in eukaryotic cell nucleus is lamin. Lamins can assemble into a two-dimensional protein meshwork at nuclear periphery, known as lamina, which provides rigidity and shape to nucleus. Mutations lamin that alter structure lamina underlie laminopathic diseases, including Hutchinson–Gilford Progeria Syndrome (HGPS). Experiments have shown that, compared healthy cells, supramolecular structures (e.g., protofilaments) thicker HGPS, where they form highly stable nematic microdomains reminiscent liquid crystals. This significantly alters morphological mechanical properties In this study, we investigate aggregation fibrous their dissociation kinetics from periphery by modeling them coarse-grained, rod-like polymer chains confined within rigid spherical shell. Our model reproduces formation multidirectional domains surface reduced observed HGPS nuclei adjusting concentration, lamin–lamin (head–tail), lamin–shell association strengths. While phase requires relatively strong affinity under any non-vanishing inter-lamin attraction, thickness layer primarily controlled head–tail strength model. Furthermore, unbinding exhibit concentration-dependent facilitated dissociation, suppressed intra-lamin interactions, diseased nuclei. Overall, our calculations reveal physical mechanisms mutations affecting native interactions concentration could lead an abnormal diseases.

Язык: Английский

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Nuclear Softness Promotes the Metastatic Potential of Large-Nucleated Colorectal Cancer Cells via the ErbB4-Akt1-Lamin A/C Signaling Pathway

International Journal of Biological Sciences, Год журнала: 2024, Номер 20(7), С. 2748 - 2762

Опубликована: Янв. 1, 2024

Abnormal nuclear enlargement is a diagnostic and physical hallmark of malignant tumors.Large nuclei are positively associated with an increased risk developing metastasis; however, large nucleus inevitably more resistant to cell migration due its size.The present study demonstrated that the size primary colorectal cancer (CRC) cells at advanced stage was larger than early stage.In addition, CRC liver metastases were those corresponding tissues.CRC sorted into large-nucleated (LNCs) small-nucleated (SNCs).Purified LNCs exhibited greater constricted migratory metastatic capacity SNCs in vitro vivo.Mechanistically, ErbB4 highly expressed LNCs, which phosphorylated lamin A/C serine 22 via ErbB4-Akt1 signaling pathway.Furthermore, level negative determinant stiffness.Taken together, possessed potential ErbB4-Akt1-mediated phosphorylation softening.These results may provide treatment strategy for tumor metastasis by targeting stiffness patients cancer, particularly CRC.

Язык: Английский

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Intermediate filaments at a glance

Journal of Cell Science, Год журнала: 2024, Номер 137(16)

Опубликована: Авг. 15, 2024

Intermediate filaments (IFs) comprise a large family of versatile cytoskeletal proteins, divided into six subtypes with tissue-specific expression patterns. IFs have wide repertoire cellular functions, including providing structural support to cells, as well active roles in mechanical and signaling pathways. Consequently, defects are associated more than 100 diseases. In this Cell Science at Glance article, we discuss the established classes their general features, functions beyond support, recent advances field. We also highlight involvement disease potential use clinical markers pathological conditions. Finally, provide our view on current knowledge gaps future directions IF

Язык: Английский

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LMNA-related muscular dystrophy: Identification of variants in alternative genes and personalized clinical translation

Frontiers in Genetics, Год журнала: 2023, Номер 14

Опубликована: Март 24, 2023

Background: Laminopathies are caused by rare alterations in LMNA , leading to a wide clinical spectrum. Though muscular dystrophy begins at early ages, disease progression is different each patient. We investigated variability laminopathy phenotypes performing targeted genetic analysis of patients diagnosed with -related identify variants alternative genes, thereby explaining phenotypic differences. Methods: analyzed 105 genes associated diseases sequencing 26 pediatric countries, any dystrophy. Family members were also clinically assessed and genetically analyzed. Results: All carried pathogenic variant . Clinical diagnoses included Emery-Dreifuss (EDMD, 13 patients), congenital (L-CMD, 11 limb-girdle 1B (LGMD1B, 2 patients). In 9 patients, 10 additional identified 8 other than Genotype-phenotype correlation showed deleterious five the nine (3 L-CMD EDMD) severe phenotypes. Conclusion: Analysis f known related close personalized assessments may help potentially onset or most progression.

Язык: Английский

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Developmental changes in nuclear lamina components during germ cell differentiation

Nucleus, Год журнала: 2024, Номер 15(1)

Опубликована: Апрель 10, 2024

The nuclear lamina (NL) changes composition for regulation of events. We investigated that occur in Drosophila oogenesis, revealing switches NL during germ cell differentiation. Germline stem cells (GSCs) express only LamB and predominantly emerin, whereas differentiating nurse LamC emerin2. A change LamC-specific localization also occurs, wherein phosphorylated redistributes to the interior oocyte, prior transcriptional reactivation meiotic genome. These support existing concepts promotes differentiation, a premise was tested. Remarkably ectopic production GSCs did not promote premature Increased levels altered internal structure, increased RNA production, reduced female fertility due defects eggshell formation. studies suggest differences between lamins are regulatory, functional, reveal an unexpected robustness level major scaffolding component NL.

Язык: Английский

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Phosphoproteomic analysis reveals the mechanisms of human umbilical cord mesenchymal stem cell-derived exosomes attenuate renal aging

Journal of Proteomics, Год журнала: 2024, Номер 310, С. 105335 - 105335

Опубликована: Окт. 20, 2024

Язык: Английский

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Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases

Cells, Год журнала: 2023, Номер 12(8), С. 1142 - 1142

Опубликована: Апрель 12, 2023

Mutations in the LMNA gene cause a collection of diseases known as laminopathies, including muscular dystrophies, lipodystrophies, and early-onset aging syndromes. The encodes A-type lamins, lamins A/C, intermediate filaments that form meshwork underlying inner nuclear membrane. Lamins have conserved domain structure consisting head, coiled-coil rod, C-terminal tail possessing an Ig-like fold. This study identified differences between two mutant distinct clinical diseases. One mutations lamin A/C p.R527P other codes p.R482W, which are typically associated with dystrophy lipodystrophy, respectively. To determine how these differentially affect muscle, we generated equivalent Drosophila Lamin C (LamC) gene, orthologue human LMNA. muscle-specific expression R527P showed cytoplasmic aggregation LamC, reduced larval muscle size, decreased motility, cardiac defects resulting adult lifespan. By contrast, R482W caused abnormal shape without change lifespan compared to controls. Collectively, studies fundamental properties clinically phenotypes, providing insights into disease mechanisms.

Язык: Английский

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Native lamin A/C proteomes and novel partners from heart and skeletal muscle in a mouse chronic inflammation model of human frailty

Frontiers in Cell and Developmental Biology, Год журнала: 2023, Номер 11

Опубликована: Окт. 23, 2023

Clinical frailty affects ∼10% of people over age 65 and is studied in a chronically inflamed (Interleukin-10 knockout; “IL10-KO”) mouse model. Frailty phenotypes overlap the spectrum diseases (“laminopathies”) caused by mutations LMNA . encodes nuclear intermediate filament proteins lamin A C (“lamin A/C”), important for tissue-specific signaling, metabolism chromatin regulation. We hypothesized that wildtype A/C associations with partners are perturbed chronic inflammation, potentially contributing to dysfunction frailty. To test this idea we immunoprecipitated native associated from skeletal muscle, hearts brains old (21–22 months) IL10-KO versus control C57Bl/6 female mice, labeled Tandem Mass Tags identification quantitation mass spectrometry. identified 502 candidate lamin-binding 340 heart, including 62 both tissues. Candidates included phenotype-relevant Perm1 Fam210a, membrane protein Tmem38a, required muscle-specific genome organization. These most other candidates were unaffected IL10-KO, but still as potential A/C-binding heart or muscle. subset (21 30 heart) showed significantly different A/C-association an tissue ( p < 0.05), AldoA Gins3 affected Lmcd1 Fabp4 screen binding, eleven plus prelamin emerin controls arrayed synthetic 20-mer peptides (7-residue stagger) incubated recombinant purified “tail” residues 385–646 under relatively stringent conditions. detected strong binding solvent exposed Lmcd1, AldoA, Perm1, plausible Csrp3 (muscle LIM protein). results validated proteomes sources four genes Emery-Dreifuss muscular dystrophy (CSRP3, LMCD1, ALDOA, PERM1), support A-interactive molecular role Tmem38A, supported hypothesis interactions at least two (AldoA transcription factor muscle) altered model

Язык: Английский

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The Paradox of Nuclear Lamins in Pathologies: Apparently Controversial Roles Explained by Tissue-Specific Mechanobiology

Cells, Год журнала: 2022, Номер 11(14), С. 2194 - 2194

Опубликована: Июль 13, 2022

The nuclear lamina is a complex meshwork of intermediate filaments (lamins) that located beneath the inner membrane and surrounding nucleoplasm. lamins exert both structural functional roles in nucleus and, by interacting with several proteins, are involved wide range cellular activities. Due their pivotal basic processes, lamin gene mutations, or modulations expression, often associated pathological conditions, ranging from rare genetic diseases, such as laminopathies, to cancer. Although substantial amount literature describes effects mediated deregulation lamins, some apparently controversial results have been reported, which may appear conflict each other. In this context, we herein provide our explanation “controversy”, which, opinion, derives tissue-specific expression close correlation mechanotransduction could be very different, even opposite, depending on specific mechanical conditions should not compared (a tissue vs. another tissue, vivo studies cell cultures glass/plastic supports, etc.). Moreover, stressed relevance considering reproducing “mechano-environment” vitro experimentation. Indeed, when primary cells collected patients donors maintained culture, signals deriving canonical experimental procedures culturing alter thereby profoundly modifying assessed type, cases too much, origin.

Язык: Английский

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Nuclear size rectification: A potential new therapeutic approach to reduce metastasis in cancer

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Окт. 10, 2022

Research on metastasis has recently regained considerable interest with the hope that single cell technologies might reveal most critical changes support tumor spread. However, it is possible part of answer been visible through microscope for close to 200 years. Changes in nuclear size characteristically occur many cancer types when cells metastasize. This was initially discarded as contributing metastatic spread because, depending types, both increases and decreases could correlate increased metastasis. recent work mechanics connectivity between chromatin, nucleoskeleton, cytoskeleton indicate this can have profound impacts mobility invasiveness. Critically, a study found reversing type-dependent correlated reduced migration invasion. Accordingly, seems appropriate now revisit contributory roles

Язык: Английский

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