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Severe congenital myasthenic syndromes caused by agrin mutations affecting secretion by motoneurons.Acta Neuropathologica Oct 2022Congenital myasthenic syndromes (CMS) are predominantly characterized by muscle weakness and fatigability and can be caused by a variety of mutations in genes required...
Congenital myasthenic syndromes (CMS) are predominantly characterized by muscle weakness and fatigability and can be caused by a variety of mutations in genes required for neuromuscular junction formation and maintenance. Among them, AGRN encodes agrin, an essential synaptic protein secreted by motoneurons. We have identified severe CMS patients with uncharacterized p.R1671Q, p.R1698P and p.L1664P mutations in the LG2 domain of agrin. Overexpression in primary motoneurons cultures in vitro and in chick spinal motoneurons in vivo revealed that the mutations modified agrin trafficking, leading to its accumulation in the soma and/or in the axon. Expression of mutant agrins in cultured cells demonstrated accumulation of agrin in the endoplasmic reticulum associated with induction of unfolded protein response (UPR) and impaired secretion in the culture medium. Interestingly, evaluation of the specific activity of individual agrins on AChR cluster formation indicated that when secreted, mutant agrins retained a normal capacity to trigger the formation of AChR clusters. To confirm agrin accumulation and secretion defect, iPS cells were derived from a patient and differentiated into motoneurons. Patient iPS-derived motoneurons accumulated mutant agrin in the soma and increased XBP1 mRNA splicing, suggesting UPR activation. Moreover, co-cultures of patient iPS-derived motoneurons with myotubes confirmed the deficit in agrin secretion and revealed a reduction in motoneuron survival. Altogether, we report the first mutations in AGRN gene that specifically affect agrin secretion by motoneurons. Interestingly, the three patients carrying these mutations were initially suspected of spinal muscular atrophy (SMA). Therefore, in the presence of patients with a clinical presentation of SMA but without mutation in the SMN1 gene, it can be worth to look for mutations in AGRN.
Topics: Agrin; Humans; Motor Neurons; Mutation; Myasthenic Syndromes, Congenital; Neuromuscular Junction
PubMed: 35948834
DOI: 10.1007/s00401-022-02475-8 -
Current Opinion in Neurology Feb 2020Ocular myasthenia gravis (OMG) is a complex condition with heterogenous phenotypes and ill-defined diagnostic criteria. Understanding concomitant risk factors and... (Review)
Review
PURPOSE OF REVIEW
Ocular myasthenia gravis (OMG) is a complex condition with heterogenous phenotypes and ill-defined diagnostic criteria. Understanding concomitant risk factors and autoimmune serology can help inform prognosis for generalization and guide treatment.
RECENT FINDINGS
Although antibodies to acetylcholine receptors or muscle-specific kinase likely increase risk of generalization, they are less frequent in OMG. Patients without either antibody tend to have a milder disease process and often have variable antibodies to other end-plate proteins such as LRP4, agrin, or cortactin. The treatment of OMG begins with pyridostigmine and is supplemented by oral prednisone if treatment-resistant or high risk for generalization. Variable oral prednisone regimens have been used with success and further immunosuppression may be best achieved with mycophenolate mofetil and azathioprine. Checkpoint inhibitor-induced myasthenia gravis is increasingly recognized and likely has high rates of mortality associated with myocarditis.
SUMMARY
Our understanding of OMG and its variable phenotypes continues to evolve. Autoantibody testing increasingly provides valuable diagnostic and prognostic information. Despite these improvements, a lack of quality treatment trials creates significant challenges for evidence-based management guidelines.
Topics: Autoantibodies; Disease Progression; Humans; Myasthenia Gravis; Prognosis; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic
PubMed: 31789705
DOI: 10.1097/WCO.0000000000000775 -
Cells Jul 2019Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine... (Review)
Review
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different pathogenic mechanisms to altered tissue architecture and reduced densities or functionality of AChRs, reduced neuromuscular transmission, and therefore a severe fatigable skeletal muscle weakness. In this review, we give an overview of the history and clinical aspects of MG, with a focus on the structure and function of myasthenic autoantigens at the NMJ and how they are affected by the autoantibodies' pathogenic mechanisms. Furthermore, we give a short overview of the cells that are implicated in the production of the autoantibodies and briefly discuss diagnostic challenges and treatment strategies.
Topics: Agrin; Animals; Autoantibodies; Autoantigens; Humans; LDL-Receptor Related Proteins; Muscle, Skeletal; Myasthenia Gravis; Neuromuscular Junction; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic; Receptors, Nicotinic
PubMed: 31269763
DOI: 10.3390/cells8070671 -
The Journal of International Medical... May 2021This study examined the role of agrin in the development of cholangiocarcinoma (CCA).
OBJECTIVE
This study examined the role of agrin in the development of cholangiocarcinoma (CCA).
METHODS
Western blotting was performed to detect the expression of target genes. The correlation between agrin expression and prognosis was analyzed using the Kaplan-Meier method. Proliferation, migration, invasion, and tumorigenesis were examined in CCA cells and tissues using the Cell Counting Kit-8 assay, cell cycle analysis, transwell migration assay, and nude mouse tumorigenicity assay , respectively.
RESULTS
Agrin expression was significantly upregulated in CCA tissues compared with that in adjacent non-tumor tissues, and agrin expression was correlated with poorer tumor characteristics such as portal vein tumor thrombus, intrahepatic metastasis, and worse survival. Forced agrin expression in CCA cells apparently promoted proliferation, colony formation, migration, invasion, and cell cycle progression, but agrin depletion had the opposite effects. Furthermore, agrin-depleted CCA cells developed fewer and smaller tumors than control cells . Mechanistic analyses indicated that agrin activated the Hippo signaling pathway and induced the translocation of YAP to the nucleus.
CONCLUSIONS
Agrin promoted CCA progression by activating the Hippo signaling pathway, suggesting its promise as a target for CCA therapy.
Topics: Agrin; Animals; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cholangiocarcinoma; Gene Expression Regulation, Neoplastic; Mice; Prognosis
PubMed: 34018826
DOI: 10.1177/03000605211009722 -
Cancer Metastasis Reviews Sep 2020A dynamic mucosal layer shields the epithelial cells lining the body cavities and is made up of high molecular weight, heavily glycosylated, multidomain proteins called... (Review)
Review
A dynamic mucosal layer shields the epithelial cells lining the body cavities and is made up of high molecular weight, heavily glycosylated, multidomain proteins called mucins. Mucins, broadly grouped into transmembrane and secreted mucins, are the first responders to any mechanical or chemical insult to the epithelia and help maintain tissue homeostasis. However, their intrinsic properties to protect and repair the epithelia are exploited during oncogenic processes, where mucins are metamorphosed to aid the tumor cells in their malignant journey. Diverse domains, like the variable number tandem repeats (VNTR), sea urchin sperm protein enterokinase and agrin (SEA), adhesion-associated domain (AMOP), nidogen-like domain (NIDO), epidermal growth factor-like domain (EGF), and von Willebrand factor type D domain (vWD) on mucins, including MUC1, MUC4, MUC5AC, MUC5B, and MUC16, have been shown to facilitate cell-to-cell and cell-to-matrix interactions, and cell-autonomous signaling to promote tumorigenesis and distant dissemination of tumor cells. Several obstacles have limited the study of mucins, including technical difficulties in working with these huge glycoproteins, the dearth of scientific tools, and lack of animal models; thus, the tissue-dependent and domain-specific roles of mucins during mucosal protection, chronic inflammation, tumorigenesis, and hematological dissemination of malignant cells are still unclear. Future studies should try to integrate information on the rheological, molecular, and biological characteristics of mucins to comprehensively delineate their pathophysiological role and evaluate their suitability as targets in future diagnostic and therapeutic strategies.
Topics: Animals; Humans; Mucins; Neoplasm Metastasis; Neoplasms; Protein Domains
PubMed: 32488403
DOI: 10.1007/s10555-020-09896-5 -
Developmental Neurobiology Aug 2014Neuromuscular junction (NMJ) is a cholinergic synapse where motor neurons elicit muscle contraction. Agrin and its coreceptors LRP4 and MuSK are critical for vertebrate... (Review)
Review
Neuromuscular junction (NMJ) is a cholinergic synapse where motor neurons elicit muscle contraction. Agrin and its coreceptors LRP4 and MuSK are critical for vertebrate NMJ formation. This paper reviews recent evidence for Wnts and Wnt signaling molecules in NMJ formation including a possible retrograde mechanism by muscle β-catenin. We also present data that Wnt3a, 7a, 8a and 10b could inhibit agrin-mediated AChR clustering. Together with the stimulating effect of Wnt9a, 9b, 10b, 11 and 16 on AChR clustering in the absence of agrin, these results suggest diverse roles for Wnt ligands in NMJ development.
Topics: Agrin; Animals; Cell Differentiation; Humans; Neuromuscular Junction; Synapses; Vertebrates; Wnt Signaling Pathway
PubMed: 24838312
DOI: 10.1002/dneu.22190 -
Frontiers in Molecular Neuroscience 2017The biological fates of the key initiator of Alzheimer's disease (AD), the amyloid precursor protein (APP), and a family of lipoprotein receptors, the low-density... (Review)
Review
The biological fates of the key initiator of Alzheimer's disease (AD), the amyloid precursor protein (APP), and a family of lipoprotein receptors, the low-density lipoprotein (LDL) receptor-related proteins (LRPs) and their molecular roles in the neurodegenerative disease process are inseparably interwoven. Not only does APP bind tightly to the extracellular domains (ECDs) of several members of the LRP group, their intracellular portions are also connected through scaffolds like the one established by FE65 proteins and through interactions with adaptor proteins such as X11/Mint and Dab1. Moreover, the ECDs of APP and LRPs share common ligands, most notably Reelin, a regulator of neuronal migration during embryonic development and modulator of synaptic transmission in the adult brain, and Agrin, another signaling protein which is essential for the formation and maintenance of the neuromuscular junction (NMJ) and which likely also has critical, though at this time less well defined, roles for the regulation of central synapses. Furthermore, the major independent risk factors for AD, Apolipoprotein (Apo) E and ApoJ/Clusterin, are lipoprotein ligands for LRPs. Receptors and ligands mutually influence their intracellular trafficking and thereby the functions and abilities of neurons and the blood-brain-barrier to turn over and remove the pathological product of APP, the amyloid-β peptide. This article will review and summarize the molecular mechanisms that are shared by APP and LRPs and discuss their relative contributions to AD.
PubMed: 28298885
DOI: 10.3389/fnmol.2017.00054 -
Ageing Research Reviews Jan 2023Physical inactivity (PI) is a major risk factor of chronic diseases. A major aspect of PI is loss of muscle mass and strength. The latter phenomenon significantly... (Review)
Review
Physical inactivity (PI) is a major risk factor of chronic diseases. A major aspect of PI is loss of muscle mass and strength. The latter phenomenon significantly impacts daily life and represent a major issue for global health. Understandably, skeletal muscle itself has been the major focus of studies aimed at understanding the mechanisms underlying loss of mass and strength. Relatively lesser attention has been given to the contribution of alterations in somatomotor control, despite the fact that these changes can start very early and can occur at multiple levels, from the cortex down to the neuromuscular junction (NMJ). It is well known that exposure to chronic inactivity or immobilization causes a disproportionate loss of force compared to muscle mass, i.e. a loss of specific or intrinsic whole muscle force. The latter phenomenon may be partially explained by the loss of specific force of individual muscle fibres, but several other players are very likely to contribute to such detrimental phenomenon. Irrespective of the length of the disuse period, the loss of force is, in fact, more than two-fold greater than that of muscle size. It is very likely that somatomotor alterations may contribute to this loss in intrinsic muscle force. Here we review evidence that alterations of one component of somatomotor control, namely the neuromuscular junction, occur in disuse. We also discuss some of the novel players in NMJ stability (e.g., homer, bassoon, pannexin) and the importance of new established and emerging molecular markers of neurodegenerative processes in humans such as agrin, neural-cell adhesion molecule and light-chain neurofilaments.
Topics: Humans; Muscular Atrophy; Muscle, Skeletal; Neuromuscular Junction; Muscle Fibers, Skeletal
PubMed: 36471545
DOI: 10.1016/j.arr.2022.101810 -
Biochemistry Aug 2015The extracellular matrix is a dynamic repository harboring instructive cues that embody substantial regulatory dominance over many evolutionarily conserved intracellular... (Review)
Review
The extracellular matrix is a dynamic repository harboring instructive cues that embody substantial regulatory dominance over many evolutionarily conserved intracellular activities, including proliferation, apoptosis, migration, motility, and autophagy. The matrix also coordinates and parses hierarchical information, such as angiogenesis, tumorigenesis, and immunological responses, typically providing the critical determinants driving each outcome. We provide the first comprehensive review focused on proteoglycan receptors, that is, signaling transmembrane proteins that use secreted proteoglycans as ligands, in addition to their natural ligands. The majority of these receptors belong to an exclusive subset of receptor tyrosine kinases and assorted cell surface receptors that specifically bind, transduce, and modulate fundamental cellular processes following interactions with proteoglycans. The class of small leucine-rich proteoglycans is the most studied so far and constitutes the best understood example of proteoglycan-receptor interactions. Decorin and biglycan evoke autophagy and immunological responses that deter, suppress, or exacerbate pathological conditions such as tumorigenesis, angiogenesis, and chronic inflammatory disease. Basement membrane-associated heparan sulfate proteoglycans (perlecan, agrin, and collagen XVIII) represent a unique cohort and provide proteolytically cleaved bioactive fragments for modulating cellular behavior. The receptors that bind the genuinely multifactorial and multivalent proteoglycans represent a nexus in understanding basic biological pathways and open new avenues for therapeutic and pharmacological intervention.
Topics: Animals; Autophagy; Cell Transformation, Neoplastic; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Inflammation; Neovascularization, Pathologic; Proteoglycans; Receptors, Cell Surface; Signal Transduction
PubMed: 26177309
DOI: 10.1021/acs.biochem.5b00653 -
Frontiers in Cardiovascular Medicine 2022Mature cardiomyocytes are unable to proliferate, preventing the injured adult heart from repairing itself. Studies in rodents have suggested that the extracellular...
BACKGROUND
Mature cardiomyocytes are unable to proliferate, preventing the injured adult heart from repairing itself. Studies in rodents have suggested that the extracellular matrix protein agrin promotes cardiomyocyte proliferation in the developing heart and that agrin expression is downregulated shortly after birth, resulting in the cessation of proliferation. Agrin based therapies have proven successful at inducing repair in animal models of cardiac injury, however whether similar pathways exist in the human heart is unknown.
METHODS
Right ventricular (RV) biopsies were collected from 40 patients undergoing surgery for congenital heart disease and the expression of agrin and associated proteins was investigated.
RESULTS
Agrin transcripts were found in all samples and their levels were significantly negatively correlated to age ( = 0.026), as were laminin transcripts ( = 0.023), whereas no such correlation was found for the other proteins analyzed. No significant correlations for any of the proteins were found when grouping patients by their gender or pathology. Immunohistochemistry and western blots to detect and localize agrin and the other proteins under analysis in RV tissue, confirmed their presence in patients of all ages.
CONCLUSIONS
We show that agrin is progressively downregulated with age in human RV tissue but not as dramatically as has been demonstrated in mice; highlighting both similarities and differences to findings in rodents. Our results lay the groundwork for future studies exploring the potential of agrin-based therapies in the repair of damaged human hearts.
PubMed: 35355976
DOI: 10.3389/fcvm.2022.813904