scholarly journals Lamin A/C–mediated neuromuscular junction defects in Emery-Dreifuss muscular dystrophy

2009 ◽  
Vol 184 (1) ◽  
pp. 31-44 ◽  
Author(s):  
Alexandre Méjat ◽  
Valérie Decostre ◽  
Juan Li ◽  
Laure Renou ◽  
Akanchha Kesari ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Neuromuscular Junctions ◽  
Wide Spectrum ◽  
Nuclear Architecture ◽  
Lamin A ◽  
Cellular Mechanisms ◽  
Activity Dependent ◽  
Filament Type

The LMNA gene encodes lamins A and C, two intermediate filament-type proteins that are important determinants of interphase nuclear architecture. Mutations in LMNA lead to a wide spectrum of human diseases including autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD), which affects skeletal and cardiac muscle. The cellular mechanisms by which mutations in LMNA cause disease have been elusive. Here, we demonstrate that defects in neuromuscular junctions (NMJs) are part of the disease mechanism in AD-EDMD. Two AD-EDMD mouse models show innervation defects including misexpression of electrical activity–dependent genes and altered epigenetic chromatin modifications. Synaptic nuclei are not properly recruited to the NMJ because of mislocalization of nuclear envelope components. AD-EDMD patients with LMNA mutations show the same cellular defects as the AD-EDMD mouse models. These results suggest that lamin A/C–mediated NMJ defects contribute to the AD-EDMD disease phenotype and provide insights into the cellular and molecular mechanisms for the muscle-specific phenotype of AD-EDMD.

Molecular signatures of Emery–Dreifuss muscular dystrophy

2008 ◽  
Vol 36 (6) ◽  
pp. 1354-1358 ◽  
Author(s):  
Matthew A. Wheeler ◽  
Juliet A. Ellis
Keyword(s):  
Muscular Dystrophy ◽  
Dilated Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Signalling Pathways ◽  
Lamin A ◽  
Degenerative Diseases ◽  
Hypertrophic Growth ◽  
Genes Encoding

Mutations in genes encoding the nuclear envelope proteins emerin and lamin A/C lead to a range of tissue-specific degenerative diseases. These include dilated cardiomyopathy, limb-girdle muscular dystrophy and X-linked and autosomal dominant EDMD (Emery–Dreifuss muscular dystrophy). The molecular mechanisms underlying these disorders are poorly understood; however, recent work using animal models has identified a number of signalling pathways that are altered in response to the deletion of either emerin or lamin A/C or expression of Lmna mutants found in patients with laminopathies. A distinguishing feature of patients with EDMD is the association of a dilated cardiomyopathy with conduction defects. In the present article, we describe several of the pathways altered in response to an EDMD phenotype, which are known to be key mediators of hypertrophic growth, and focus on a possible role of an emerin–β-catenin interaction in the pathogenesis of this disease.

scholarly journals Cellular and molecular mechanisms underlying muscular dystrophy

2013 ◽  
Vol 201 (4) ◽  
pp. 499-510 ◽  
Author(s):  
Fedik Rahimov ◽  
Louis M. Kunkel
Keyword(s):  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Neuromuscular Disorders ◽  
Genetic Diseases ◽  
Model Systems ◽  
Cellular Mechanisms ◽  
Gene Encoding ◽  
Progressive Degeneration ◽  
Molecular Pathomechanisms

The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes.

scholarly journals Emery-Dreifuss Muscular Dystrophy-Associated Mutant Forms of Lamin A Recruit the Stress Responsive Protein Ankrd2 into the Nucleus, Affecting the Cellular Response to Oxidative Stress

2017 ◽  
Vol 42 (1) ◽  
pp. 169-184 ◽  
Author(s):  
Silvia Angori ◽  
Cristina Capanni ◽  
Georgine Faulkner ◽  
Camilla Bean ◽  
Giuseppe Boriani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Muscular Dystrophy ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Muscle Cells ◽  
Lamin A ◽  
Gene Encoding ◽  
H2o2 Treatment ◽  
Human Myotubes ◽  
Mutant Forms

Background: Ankrd2 is a stress responsive protein mainly expressed in muscle cells. Upon the application of oxidative stress, Ankrd2 translocates into the nucleus where it regulates the activity of genes involved in cellular response to stress. Emery-Dreifuss Muscular Dystrophy 2 (EDMD2) is a muscular disorder caused by mutations of the gene encoding lamin A, LMNA. As well as many phenotypic abnormalities, EDMD2 muscle cells also feature a permanent basal stress state, the underlying molecular mechanisms of which are currently unclear. Methods: Experiments were performed in EDMD2-lamin A overexpressing cell lines and EDMD2-affected human myotubes. Oxidative stress was produced by H2O2 treatment. Co-immunoprecipitation, cellular subfractionation and immunofluorescence analysis were used to validate the relation between Ankrd2 and forms of lamin A; cellular sensibility to stress was monitored by the analysis of Reactive Oxygen Species (ROS) release and cell viability. Results: Our data demonstrate that oxidative stress induces the formation of a complex between Ankrd2 and lamin A. However, EDMD2-lamin A mutants were able to bind and mislocalize Ankrd2 in the nucleus even under basal conditions. Nonetheless, cells co-expressing Ankrd2 and EDMD2-lamin A mutants were more sensitive to oxidative stress than the Ankrd2-wild type lamin A counterpart. Conclusions: For the first time, we present evidence that in muscle fibers from patients affected by EDMD2, Ankrd2 has an unusual nuclear localization. By introducing a plausible mechanism ruling this accumulation, our data hint at a novel function of Ankrd2 in the pathogenesis of EDMD2-affected cells.

scholarly journals Postsynaptic regulation of synaptic plasticity by synaptotagmin 4 requires both C2 domains

2009 ◽  
Vol 187 (2) ◽  
pp. 295-310 ◽  
Author(s):  
Cynthia F. Barber ◽  
Ramon A. Jorquera ◽  
Jan E. Melom ◽  
J. Troy Littleton
Keyword(s):  
Synaptic Plasticity ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Neuromuscular Junctions ◽  
Vesicle Fusion ◽  
Synaptic Growth ◽  
Synaptotagmin 1 ◽  
Presynaptic Vesicle ◽  
Activity Dependent

Ca2+ influx into synaptic compartments during activity is a key mediator of neuronal plasticity. Although the role of presynaptic Ca2+ in triggering vesicle fusion though the Ca2+ sensor synaptotagmin 1 (Syt 1) is established, molecular mechanisms that underlie responses to postsynaptic Ca2+ influx remain unclear. In this study, we demonstrate that fusion-competent Syt 4 vesicles localize postsynaptically at both neuromuscular junctions (NMJs) and central nervous system synapses in Drosophila melanogaster. Syt 4 messenger RNA and protein expression are strongly regulated by neuronal activity, whereas altered levels of postsynaptic Syt 4 modify synaptic growth and presynaptic release properties. Syt 4 is required for known forms of activity-dependent structural plasticity at NMJs. Synaptic proliferation and retrograde signaling mediated by Syt 4 requires functional C2A and C2B Ca2+–binding sites, as well as serine 284, an evolutionarily conserved substitution for a key Ca2+-binding aspartic acid found in other synaptotagmins. These data suggest that Syt 4 regulates activity-dependent release of postsynaptic retrograde signals that promote synaptic plasticity, similar to the role of Syt 1 as a Ca2+ sensor for presynaptic vesicle fusion.

scholarly journals Identification of a Novel Muscle A-type Lamin-interacting Protein (MLIP)

2011 ◽  
Vol 286 (22) ◽  
pp. 19702-19713 ◽  
Author(s):  
Elmira Ahmady ◽  
Shelley A. Deeke ◽  
Seham Rabaa ◽  
Lara Kouri ◽  
Laura Kenney ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscular Dystrophy ◽  
Nuclear Envelope ◽  
Molecular Mechanisms ◽  
Single Copy ◽  
Lamin A ◽  
Functional Link ◽  
Interacting Protein ◽  
Degenerative Disorders ◽  
Pml Bodies

Mutations in the A-type lamin (LMNA) gene are associated with age-associated degenerative disorders of mesenchymal tissues, such as dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and limb-girdle muscular dystrophy. The molecular mechanisms that connect mutations in LMNA with different human diseases are poorly understood. Here, we report the identification of a Muscle-enriched A-type Lamin-interacting Protein, MLIP (C6orf142 and 2310046A06rik), a unique single copy gene that is an innovation of amniotes (reptiles, birds, and mammals). MLIP encodes alternatively spliced variants (23–57 kDa) and possesses several novel structural motifs not found in other proteins. MLIP is expressed ubiquitously and most abundantly in heart, skeletal, and smooth muscle. MLIP interacts directly and co-localizes with lamin A and C in the nuclear envelope. MLIP also co-localizes with promyelocytic leukemia (PML) bodies within the nucleus. PML, like MLIP, is only found in amniotes, suggesting that a functional link between the nuclear envelope and PML bodies may exist through MLIP. Down-regulation of lamin A/C expression by shRNA results in the up-regulation and mislocalization of MLIP. Given that MLIP is expressed most highly in striated and smooth muscle, it is likely to contribute to the mesenchymal phenotypes of laminopathies.

Natural Products for Regulating Macrophages M2 Polarization

2020 ◽  
Vol 15 (7) ◽  
pp. 559-569 ◽  
Author(s):  
Zhen Chang ◽  
Youhan Wang ◽  
Chang Liu ◽  
Wanli Smith ◽  
Lingbo Kong
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Therapeutic Strategies ◽  
Research Progress ◽  
Cellular Mechanisms ◽  
Pharmacological Activities ◽  
Current Review ◽  
M2 Polarization ◽  
Macrophages Polarization ◽  
Herbal Plants

Macrophages M2 polarization have been taken as an anti-inflammatory progression during inflammation. Natural plant-derived products, with potential therapeutic and preventive activities against inflammatory diseases, have received increasing attention in recent years because of their whole regulative effects and specific pharmacological activities. However, the molecular mechanisms about how different kinds of natural compounds regulate macrophages polarization still unclear. Therefore, in the current review, we summarized the detailed research progress on the active compounds derived from herbal plants with regulating effects on macrophages, especially M2 polarization. These natural occurring compounds including flavonoids, terpenoids, glycosides, lignans, coumarins, alkaloids, polyphenols and quinones. In addition, we extensively discussed the cellular mechanisms underlying the M2 polarization for each compound, which could provide potential therapeutic strategies aiming macrophages M2 polarization.

scholarly journals Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control

2021 ◽  
Vol 22 (13) ◽  
pp. 6669
Author(s):  
Byongsun Lee ◽  
Seungjae Lee ◽  
Younggwang Lee ◽  
Yongjin Park ◽  
Jaekyung Shim
Keyword(s):  
Muscular Dystrophy ◽  
Nuclear Membrane ◽  
Target Genes ◽  
Janus Kinase ◽  
C2c12 Cells ◽  
Specific Gene ◽  
Lamin A ◽  
Stat3 Signaling ◽  
Exact Function ◽  
Muscle Homeostasis

Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery-Dreifuss muscular dystrophy (EDMD). There has been accumulating evidence that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has still less revealing. Here, we have shown that emerin downregulates signal transducers and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus-kinase (JAK). Deletion mutation experiments showed that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacted directly and co-localized with STAT3 in the nuclear membrane. Emerin knockdown induced STAT3 target genes Bcl2 and Survivin to increase cell survival signals and suppress hydrogen peroxide-induced cell death in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin by assembling with BAF and lamin A/C acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induced STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and could be a new therapeutic target for treatment.

scholarly journals Lamin A/C Is Dispensable to Mechanical Repression of Adipogenesis

2021 ◽  
Vol 22 (12) ◽  
pp. 6580
Author(s):  
Matthew Goelzer ◽  
Amel Dudakovic ◽  
Melis Olcum ◽  
Buer Sen ◽  
Engin Ozcivici ◽  
...  
Keyword(s):  
Cell Structure ◽  
Nuclear Architecture ◽  
Focal Adhesions ◽  
Protein Translation ◽  
Lamin A ◽  
Transcriptional Level ◽  
Rna Seq ◽  
Interferon Signaling ◽  
Regulate Protein ◽  
Low Intensity Vibration

Mesenchymal stem cells (MSCs) maintain the musculoskeletal system by differentiating into multiple lineages, including osteoblasts and adipocytes. Mechanical signals, including strain and low-intensity vibration (LIV), are important regulators of MSC differentiation via control exerted through the cell structure. Lamin A/C is a protein vital to the nuclear architecture that supports chromatin organization and differentiation and contributes to the mechanical integrity of the nucleus. We investigated whether lamin A/C and mechanoresponsiveness are functionally coupled during adipogenesis in MSCs. siRNA depletion of lamin A/C increased the nuclear area, height, and volume and decreased the circularity and stiffness. Lamin A/C depletion significantly decreased markers of adipogenesis (adiponectin, cellular lipid content) as did LIV treatment despite depletion of lamin A/C. Phosphorylation of focal adhesions in response to mechanical challenge was also preserved during loss of lamin A/C. RNA-seq showed no major adipogenic transcriptome changes resulting from LIV treatment, suggesting that LIV regulation of adipogenesis may not occur at the transcriptional level. We observed that during both lamin A/C depletion and LIV, interferon signaling was downregulated, suggesting potentially shared regulatory mechanism elements that could regulate protein translation. We conclude that the mechanoregulation of adipogenesis and the mechanical activation of focal adhesions function independently from those of lamin A/C.

scholarly journals Early alterations of neurovascular unit in the retina in mouse models of tauopathy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Fan Xia ◽  
Yonju Ha ◽  
Shuizhen Shi ◽  
Yi Li ◽  
Shengguo Li ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Leukocyte Adhesion ◽  
Neurovascular Unit ◽  
Integrated Analysis ◽  
Therapeutic Effects ◽  
Retinal Ganglion ◽  
Potential Biomarker

AbstractThe retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

scholarly journals Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease

2021 ◽  
Vol 10 (8) ◽  
pp. 1555
Author(s):  
Ágoston Patthy ◽  
János Murai ◽  
János Hanics ◽  
Anna Pintér ◽  
Péter Zahola ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Brain Structures ◽  
Specific Information ◽  
Cellular Mechanisms ◽  
Monoaminergic System ◽  
Monoaminergic Neurons

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, receives massive afferents from caudal brain structures, which do not only convey specific information but powerfully tune ensemble activity. Moreover, there is evidence that the start of AD is subcortical. The brainstem harbors monoamine systems, which establish a dense innervation in both allo- and neocortex. Monoaminergic synapses can co-release neuropeptides either by precisely terminating on cortical neurons or, when being “en passant”, can instigate local volume transmission. Especially due to its early damage, malfunction of the ascending monoaminergic system emerges as an early sign and possible trigger of AD. This review summarizes the involvement and cascaded impairment of brainstem monoaminergic neurons in AD and discusses cellular mechanisms that lead to their dysfunction. We highlight the significance and therapeutic challenges of transmitter co-release in ascending activating system, describe the role and changes of local connections and distant afferents of brainstem nuclei in AD, and summon the rapidly increasing diagnostic window during the last few years.

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