429 results match your criteria achr clusters

In sickness and in health: when myasthenia gravis is a conjugal matter.

Neurol Sci 2021 May 7;42(5):2099-2101. Epub 2021 Jan 7.

Institute of Neurology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Largo A. Gemelli, 8, 00168, Rome, Italy.

Objective: Genes and environment contribute to the multifactorial etiology of autoimmune diseases. Familial clusters of autoimmune diseases are often observed among first-degree relatives sharing the same genetic background and environmental exposure. Rarer is the occurrence of the same autoimmune diseases in non-consanguineous spouses. Read More

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Pelvic floor muscle function recovery using biofabricated tissue constructs with neuromuscular junctions.

Acta Biomater 2021 02 13;121:237-249. Epub 2020 Dec 13.

Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1094, USA. Electronic address:

Damages in pelvic floor muscles often cause dysfunction of the entire pelvic urogenital system, which is clinically challenging. A bioengineered skeletal muscle construct that mimics structural and functional characteristics of native skeletal muscle could provide a therapeutic option to restore normal muscle function. However, most of the current bioengineered muscle constructs are unable to provide timely innervation necessary for successful grafting and functional recovery. Read More

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February 2021

Myasthenia Gravis With Antibodies Against Muscle Specific Kinase: An Update on Clinical Features, Pathophysiology and Treatment.

Front Mol Neurosci 2020 2;13:159. Epub 2020 Sep 2.

Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.

Muscle Specific Kinase myasthenia gravis (MuSK-MG) is an autoimmune disease that impairs neuromuscular transmission leading to generalized muscle weakness. Compared to the more common myasthenia gravis with antibodies against the acetylcholine receptor (AChR), MuSK-MG affects mainly the bulbar and respiratory muscles, with more frequent and severe myasthenic crises. Treatments are usually less effective with the need for prolonged, high doses of steroids and other immunosuppressants to control symptoms. Read More

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September 2020

Grp94 Regulates the Recruitment of Aneural AChR Clusters for the Assembly of Postsynaptic Specializations by Modulating ADF/Cofilin Activity and Turnover.

eNeuro 2020 Sep/Oct;7(5). Epub 2020 Sep 8.

School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong

Temperature is a physiological factor that affects neuronal growth and synaptic homeostasis at the invertebrate neuromuscular junctions (NMJs); however, whether temperature stress could also regulate the structure and function of the vertebrate NMJs remains unclear. In this study, we use primary cultures as a vertebrate model system for investigating the involvement of heat shock protein 90 (HSP90) family of stress proteins in NMJ development. First, cold temperature treatment or HSP90 inhibition attenuates the formation of aneural acetylcholine receptor (AChR) clusters, but increases their stability after they are formed, in cultured muscles. Read More

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September 2020

HDAC6 regulates microtubule stability and clustering of AChRs at neuromuscular junctions.

J Cell Biol 2020 08;219(8)

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Microtubules (MTs) are known to be post-translationally modified at the neuromuscular junction (NMJ), hence increasing their stability. To date however, the function(s) of the dynamic MT network and its relative stability in the formation and maintenance of NMJs remain poorly described. Stabilization of the MT is dependent in part on its acetylation status, and HDAC6 is capable of reversing this post-translational modification. Read More

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AChR antibodies show a complex interaction with human skeletal muscle cells in a transcriptomic study.

Sci Rep 2020 07 8;10(1):11230. Epub 2020 Jul 8.

Department of Clinical Medicine, University of Bergen, Bergen, Norway.

Acetylcholine receptor (AChR) antibodies are the most important pathogenic marker in patients with myasthenia gravis (MG). The antibodies bind to AChRs on the postsynaptic membrane, and this leads to receptor degradation, destruction, or functional blocking with impaired signal at the neuromuscular junction. In this study, we have explored the effects of AChR antibodies binding to mature human myotubes with agrin-induced AChR clusters and pathways relevant for AChR degradation using bulk RNA sequencing. Read More

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Engineering 3D skeletal muscle primed for neuromuscular regeneration following volumetric muscle loss.

Biomaterials 2020 10 2;255:120154. Epub 2020 Jun 2.

Translational Tissue Engineering Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA; Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Materials Science & Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Institute for NanoBioTechnology (INBT), Johns Hopkins University School of Engineering, Baltimore, MD 21218, USA. Electronic address:

Volumetric muscle loss (VML) overwhelms the native regenerative capabilities of skeletal muscle and has few effective treatments to regain lost muscle mass and function. Tissue engineered muscle constructs designed to promote neuromuscular regeneration are a promising therapeutic avenue. To date, there has been no engineered muscle construct for VML treatment that has incorporated a pharmacologic agent to promote neuromuscular regeneration. Read More

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October 2020

CTGF/CCN2 facilitates LRP4-mediated formation of the embryonic neuromuscular junction.

EMBO Rep 2020 08 17;21(8):e48462. Epub 2020 Jun 17.

Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.

At the neuromuscular junction (NMJ), lipoprotein-related receptor 4 (LRP4) mediates agrin-induced MuSK phosphorylation that leads to clustering of acetylcholine receptors (AChRs) in the postsynaptic region of the skeletal muscle. Additionally, the ectodomain of LRP4 is necessary for differentiation of the presynaptic nerve terminal. However, the molecules regulating LRP4 have not been fully elucidated yet. Read More

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Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability.

Front Mol Neurosci 2020 28;13:86. Epub 2020 May 28.

Neurological Center, Kanazawa-Nishi Hospital, Kanazawa, Japan.

Myasthenia gravis (MG) is a disease of the postsynaptic neuromuscular junction (NMJ) where nicotinic acetylcholine (ACh) receptors (AChRs) are targeted by autoantibodies. Search for other pathogenic antigens has detected the antibodies against muscle-specific tyrosine kinase (MuSK) and low-density lipoprotein-related protein 4 (Lrp4), both causing pre- and post-synaptic impairments. Agrin is also suspected as a fourth pathogen. Read More

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Phosphorylation of α-dystrobrevin is essential for αkap accumulation and acetylcholine receptor stability.

J Biol Chem 2020 07 12;295(31):10677-10688. Epub 2020 Jun 12.

Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA

The maintenance of a high density of the acetylcholine receptor (AChR) is the hallmark of the neuromuscular junction. Muscle-specific anchoring protein (αkap) encoded within the calcium/calmodulin-dependent protein kinase IIα (CAMK2A) gene is essential for the maintenance of AChR clusters both and in cultured muscle cells. The underlying mechanism by which αkap is maintained and regulated remains unknown. Read More

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Roles of tyrosine kinases and phosphatases in the formation and dispersal of acetylcholine receptor clusters.

Neurosci Lett 2020 08 16;733:135054. Epub 2020 May 16.

Division of Life Science, the Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong Special Administrative Region; College of Life Science, National Tsing Hua University, Hsinchu, Taiwan, ROC. Electronic address:

The formation of acetylcholine receptor (AChR) clusters at the postsynaptic muscle membrane in response to motor innervation is a key event in the development of the neuromuscular junction. The synaptic AChR clustering process is initiated by motor axon-released agrin, which activates a tyrosine kinase-based signaling pathway to cause AChR aggregation. In cultured muscle cells, AChR clustering is elicited by diverse nonneural signals, and this process is also mediated by tyrosine kinases. Read More

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Congenital myasthenic syndrome-associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner.

JCI Insight 2020 04 9;5(7). Epub 2020 Apr 9.

Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.

Congenital myasthenic syndromes (CMS) are caused by mutations in molecules expressed at the neuromuscular junction. We report clinical, structural, ultrastructural, and electrophysiologic features of 4 CMS patients with 6 heteroallelic variants in AGRN, encoding agrin. One was a 7. Read More

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Site-directed MT1-MMP trafficking and surface insertion regulate AChR clustering and remodeling at developing NMJs.

Elife 2020 03 24;9. Epub 2020 Mar 24.

School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

At vertebrate neuromuscular junctions (NMJs), the synaptic basal lamina contains different extracellular matrix (ECM) proteins and synaptogenic factors that induce and maintain synaptic specializations. Here, we report that podosome-like structures (PLSs) induced by ubiquitous ECM proteins regulate the formation and remodeling of acetylcholine receptor (AChR) clusters via focal ECM degradation. Mechanistically, ECM degradation is mediated by PLS-directed trafficking and surface insertion of membrane-type 1 matrix metalloproteinase (MT1-MMP) to AChR clusters through microtubule-capturing mechanisms. Read More

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An improved method for culturing myotubes on laminins for the robust clustering of postsynaptic machinery.

Sci Rep 2020 03 11;10(1):4524. Epub 2020 Mar 11.

Laboratory of Synaptogenesis, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.

Motor neurons form specialized synapses with skeletal muscle fibers, called neuromuscular junctions (NMJs). Cultured myotubes are used as a simplified in vitro system to study the postsynaptic specialization of muscles. The stimulation of myotubes with the glycoprotein agrin or laminin-111 induces the clustering of postsynaptic machinery that contains acetylcholine receptors (AChRs). Read More

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Tumor necrosis factor alpha mediates neuromuscular synapse elimination.

Cell Discov 2020 3;6. Epub 2020 Mar 3.

1School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210 China.

During the development of mammalian neuromuscular junction (NMJ), the original supernumerary axon inputs are gradually eliminated, finally leaving each muscle fiber innervated by a single axon terminal. However, the molecular cues that mediate the elimination of redundant axon inputs remain unclear. Here we show that tumor necrosis factor-α (TNFα) expressed in postsynaptic muscle cells plays an important role in presynaptic axonal elimination at the NMJ. Read More

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Evaluation of a conducting elastomeric composite material for intramuscular electrode application.

Acta Biomater 2020 02 18;103:81-91. Epub 2019 Dec 18.

Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, United States; Center for Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, United States; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address:

Electrical stimulation of the muscle has been proven efficacious in preventing atrophy and/or reanimating paralyzed muscles. Intramuscular electrodes made from metals have significantly higher Young's Moduli than the muscle tissues, which has the potential to cause chronic inflammation and decrease device performance. Here, we present an intramuscular electrode made from an elastomeric conducting polymer composite consisting of PEDOT-PEG copolymer, silicone and carbon nanotubes (CNT) with fluorosilicone insulation. Read More

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February 2020

SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody.

Neurol Neuroimmunol Neuroinflamm 2020 01 12;7(1). Epub 2019 Dec 12.

From the Department of Clinical Neurosciences (S.H., M.C., M.W., P.M.R.C., J.C., D.B., A.V.), Weatherall Institute of Molecular Medicine and Nuffield, University of Oxford, UK; Department of Clinical and Experimental Medicine (A.D.R., M.M., R.R.), Neurology Unit, Pisa; and Department of Neuroscience (A.E.), Catholic University, Rome, Italy.

Objective: To determine whether an SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitor would increase muscle-specific kinase (MuSK) phosphorylation and override the inhibitory effect of MuSK-antibodies (Abs).

Methods: The effect of the SHP2 inhibitor NSC-87877 on MuSK phosphorylation and AChR clustering was tested in C2C12 myotubes with 31 MuSK-myasthenia gravis (MG) sera and purified MuSK-MG IgG4 preparations.

Results: In the absence of MuSK-MG Abs, NSC-87877 increased MuSK phosphorylation and the number of AChR clusters in C2C12 myotubes in vitro and in DOK7-overexpressing C2C12 myotubes that form spontaneous AChR clusters. Read More

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January 2020

Postsynaptic Ca1.1-driven calcium signaling coordinates presynaptic differentiation at the developing neuromuscular junction.

Sci Rep 2019 12 5;9(1):18450. Epub 2019 Dec 5.

Department of Physiology and Medical Physics, Medical University Innsbruck, 6020, Innsbruck, Austria.

Proper formation of neuromuscular synapses requires the reciprocal communication between motor neurons and muscle cells. Several anterograde and retrograde signals involved in neuromuscular junction formation are known. However the postsynaptic mechanisms regulating presynaptic differentiation are still incompletely understood. Read More

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December 2019

Loss of Protein Kinase Csnk2b/CK2β at Neuromuscular Junctions Affects Morphology and Dynamics of Aggregated Nicotinic Acetylcholine Receptors, Neuromuscular Transmission, and Synaptic Gene Expression.

Cells 2019 08 20;8(8). Epub 2019 Aug 20.

Institute of Biochemistry, Medical Faculty, Friedrich-Alexander-University of Erlangen-Nürnberg, |91054 Erlangen, Germany.

The protein kinase Csnk2/CK2 is important for cell proliferation, differentiation, and survival. Previously, we showed that CK2 binds distinctive proteins at neuromuscular junctions (NMJs) of mice and phosphorylates some of them. CK2 likely stabilizes clustered nicotinic acetylcholine receptors (AChRs). Read More

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α-Calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles.

Mol Metab 2019 10 3;28:91-106. Epub 2019 Jul 3.

Department of Physiology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. Electronic address:

Objective: Although it is well established that a-calcitonin gene-related peptide (CGRP) stabilizes muscle-type cholinergic receptors nicotinic subunits (AChR), the underlying mechanism by which this neuropeptide regulates muscle protein metabolism and neuromuscular junction (NMJ) morphology is unclear.

Methods: To elucidate the mechanisms how CGRP controls NMJ stability in denervated mice skeletal muscles, we carried out physiological, pharmacological, and molecular analyses of atrophic muscles induced by sciatic nerve transection.

Results: Here, we report that CGRP treatment in vivo abrogated the deleterious effects on NMJ upon denervation (DEN), an effect that was associated with suppression of skeletal muscle proteolysis, but not stimulation of protein synthesis. Read More

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October 2019

Loss of mitochondrial protein CHCHD10 in skeletal muscle causes neuromuscular junction impairment.

Hum Mol Genet 2020 07;29(11):1784-1796

The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang, China 310003.

The neuromuscular junction (NMJ) is a synapse between motoneurons and skeletal muscles to control motor behavior. Acetylcholine receptors (AChRs) are restricted at the synaptic region for proper neurotransmission. Mutations in the mitochondrial CHCHD10 protein have been identified in multiple neuromuscular disorders; however, the physiological roles of CHCHD10 at NMJs remain elusive. Read More

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Development of a mouse nerve-transfer model for brachial plexus injury.

Biomed Res 2019 ;40(3):115-123

Division of Gross Anatomy and Morphogenesis, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences.

Nerve transfer involves the use of a portion of a healthy nerve to repair an injured nerve, and the process has been used to alleviate traumatic brachial plexus injuries in humans. Study of the neural mechanisms that occur during nerve transfer, however, requires the establishment of reliable experimental models. In this study, we developed an ulnar-musculocutaneous nerve-transfer model wherein the biceps muscle of a mouse was re-innervated using a donor ulnar nerve. Read More

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December 2019

Rapsyn facilitates recovery from desensitization in fetal and adult acetylcholine receptors expressed in a muscle cell line.

J Physiol 2019 07 17;597(14):3713-3725. Epub 2019 Jun 17.

Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Key Points: The physiological significance of the developmental switch from fetal to adult acetylcholine receptors in muscle (AChRs) and the functional impact of AChR clustering by rapsyn are not well studied. Using patch clamp experiments, we show that recovery from desensitization is faster in the adult AChR isoform. Recovery from desensitization is determined by the AChR isoform-specific cytoplasmic M3-M4 domain. Read More

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Correct expression and localization of collagen XIII are crucial for the normal formation and function of the neuromuscular system.

Eur J Neurosci 2019 06 8;49(11):1491-1511. Epub 2019 Feb 8.

Faculty of Biochemistry and Molecular Medicine, Center for Cell-Matrix Research, Biocenter Oulu, University of Oulu, Oulu, Finland.

Transmembrane collagen XIII has been linked to maturation of the musculoskeletal system. Its absence in mice (Col13a1 ) results in impaired neuromuscular junction (NMJ) differentiation and function, while transgenic overexpression (Col13a1 ) leads to abnormally high bone mass. Similarly, loss-of-function mutations in COL13A1 in humans produce muscle weakness, decreased motor synapse function and mild dysmorphic skeletal features. Read More

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Differential effects of spinal motor neuron-derived and skeletal muscle-derived Rspo2 on acetylcholine receptor clustering at the neuromuscular junction.

Sci Rep 2018 09 11;8(1):13577. Epub 2018 Sep 11.

Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.

We recently reported that R-spondin 2 (Rspo2), a secreted activator of Wnt/β-catenin signaling, promotes acetylcholine receptor (AChR) clustering and neuromuscular junction (NMJ) formation via its receptor, Lgr5. Rspo2 is expressed highly in spinal motor neurons (SMNs) and marginally in the skeletal muscle, but the origin of Rspo2 at the NMJ remains elusive. We rescued Rspo2-deficient (Rspo2) mice by specifically expressing Rspo2 in the skeletal muscle and SMNs. Read More

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September 2018

Sarcoglycan Alpha Mitigates Neuromuscular Junction Decline in Aged Mice by Stabilizing LRP4.

J Neurosci 2018 10 31;38(41):8860-8873. Epub 2018 Aug 31.

Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106,

During aging, acetylcholine receptor (AChR) clusters become fragmented and denervated at the neuromuscular junction (NMJ). Underpinning molecular mechanisms are not well understood. We showed that LRP4, a receptor for agrin and critical for NMJ formation and maintenance, was reduced at protein level in aged mice, which was associated with decreased MuSK tyrosine phosphorylation, suggesting compromised agrin-LRP4-MuSK signaling in aged muscles. Read More

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October 2018

Motoneuron Wnts regulate neuromuscular junction development.

Elife 2018 08 16;7. Epub 2018 Aug 16.

Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States.

The neuromuscular junction (NMJ) is a synapse between motoneurons and skeletal muscles to control motor behavior. Unlike extensively investigated postsynaptic differentiation, less is known about mechanisms of presynaptic assembly. Genetic evidence of Wnt in mammalian NMJ development was missing due to the existence of multiple Wnts and their receptors. Read More

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Balanced Rac1 activity controls formation and maintenance of neuromuscular acetylcholine receptor clusters.

J Cell Sci 2018 08 10;131(15). Epub 2018 Aug 10.

JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, College of Pharmacy, Jinan University, Guangzhou 510632, Guangdong, China

Rac1, an important Rho GTPase that regulates the actin cytoskeleton, has long been suggested to participate in acetylcholine receptor (AChR) clustering at the postsynaptic neuromuscular junction. However, how Rac1 is regulated and how it influences AChR clusters have remained unexplored. This study shows that breaking the balance of Rac1 regulation, by either increasing or decreasing its activity, led to impaired formation and maintenance of AChR clusters. Read More

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Beta-2 Adrenergic Receptor Agonists Enhance AChR Clustering in C2C12 Myotubes: Implications for Therapy of Myasthenic Disorders.

J Neuromuscul Dis 2018 ;5(2):231-240

Neurosciences Group, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford, UK.

Background: Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular transmission disorders causing fatiguable muscle weakness. ADRB2 agonists have been observed to provide therapeutic benefit where destabilisation of NMJ structures is part of the underlying pathology, such as in DOK7, COLQ and MuSK CMS as well as in slow channel syndrome. However, very little is known about the molecular mechanisms underlying the effects of ADRB2 agonists in CMS. Read More

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November 2018

Collagen VI is required for the structural and functional integrity of the neuromuscular junction.

Acta Neuropathol 2018 09 11;136(3):483-499. Epub 2018 May 11.

Department of Molecular Medicine, University of Padova, Via Ugo Bassi 58/B, 35131, Padua, Italy.

The synaptic cleft of the neuromuscular junction (NMJ) consists of a highly specialized extracellular matrix (ECM) involved in synapse maturation, in the juxtaposition of pre- to post-synaptic areas, and in ensuring proper synaptic transmission. Key components of synaptic ECM, such as collagen IV, perlecan and biglycan, are binding partners of one of the most abundant ECM protein of skeletal muscle, collagen VI (ColVI), previously never linked to NMJ. Here, we demonstrate that ColVI is itself a component of this specialized ECM and that it is required for the structural and functional integrity of NMJs. Read More

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September 2018