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The Structure of Human Neuromuscular Junctions: Some Unanswered Molecular Questions

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The Structure of Human Neuromuscular Junctions: Some Unanswered Molecular Questions International Journal of Molecular Sciences Review The Structure of Human Neuromuscular Junctions: Some Unanswered Molecular Questions Clarke R. Slater Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE1 7RU, UK; [email protected]; Tel.: +44-191-222-5954 Received: 11 September 2017; Accepted: 13 October 2017; Published: 19 October 2017 Abstract: The commands that control animal movement are transmitted from motor neurons to their target muscle cells at the neuromuscular junctions (NMJs). The NMJs contain many protein species whose role in transmission depends not only on their inherent properties, but also on how they are distributed within the complex structure of the motor nerve terminal and the postsynaptic muscle membrane. These molecules mediate evoked chemical transmitter release from the nerve and the action of that transmitter on the muscle. Human NMJs are among the smallest known and release the smallest number of transmitter “quanta”. By contrast, they have the most deeply infolded postsynaptic membranes, which help to amplify transmitter action. The same structural features that distinguish human NMJs make them particularly susceptible to pathological processes. While much has been learned about the molecules which mediate transmitter release and action, little is known about the molecular processes that control the growth of the cellular and subcellular components of the NMJ so as to give rise to its mature form. A major challenge for molecular biologists is to understand the molecular basis for the development and maintenance of functionally important aspects of NMJ structure, and thereby to point to new directions for treatment of diseases in which neuromuscular transmission is impaired. Keywords: neuromuscular junction; structure; neuromuscular transmission; human; mouse; disease 1. Why Studying the Structure of Human Neuromuscular Junctions (NMJs) Is Important The ability to move purposefully within the environment is an essential feature of the life of animals, including humans. The neuromuscular junction (NMJ) is the site where the central nervous system CNS interacts with skeletal muscle fibers and causes them to contract—where intent and purpose are converted into action. During the process of neuromuscular transmission, patterned electrical activity in a motor neuron causes the release from its terminals of a chemical transmitter which then acts on the nearby surface of the target muscle cells to cause localized electrical depolarization and the activation of contraction. Anything that impairs this complex process of signal transmission is likely to lead to muscle weakness or paralysis, and potentially to a profound deterioration of the quality of life. Many pathological conditions which are characterized by impaired neuromuscular transmission are known in humans, including those caused by mutations in more than 30 genes [1]. For many of these conditions, the available treatments are far from ideal. Efforts to improve treatment of patients with these conditions depend on understanding the factors that normally determine the efficacy of NMJ function. These factors include not only the functioning of the individual protein molecules and molecular complexes that mediate transmitter release and action, but how those complexes are localized within the complex structure of the NMJ. As a result, mutations may exert their pathogenic effect not only by altering the abundance and function of the proteins encoded by the mutated genes, but also by altering various aspects of NMJ structure. While much has been learned in recent years about the molecular basis of transmitter release and action, we still remain largely ignorant of how the structural features of the NMJ are determined. Int. J. Mol. Sci. 2017, 18, 2183; doi:10.3390/ijms18102183 www.mdpi.com/journal/ijms Int.Int. J. Mol.J. Mol. Sci. Sci.2017 2017, ,18 18,, 2183 2183 2 of 218 of 18 about the molecular basis of transmitter release and action, we still remain largely ignorant of how theIn structural this brief features review, of my the aim NMJ is toare interest determined. molecular scientists in some of the fundamental questions associatedIn this with brief trying review, to understand my aim is howto interest the structure molecular of the scientists NMJ is in regulated, some of howthe fundamental it evolved, and howquestions it responds associated to pathological with trying processes. to understand I start ho byw reviewingthe structure the of basic the NMJ properties is regulated, of the how NMJ it and neuromuscularevolved, and how transmission. it responds Ito then pathological consider proces brieflyses. how I start human by reviewing NMJs fit intothe basic the broadproperties spectrum of ofthe NMJs NMJ in and the neuromuscular animal kingdom, transmission. identifying I then some cons distinctiveider briefly feature how human of human NMJs NMJs, fit into and the broad consider howspectrum those of features NMJs in may the influenceanimal kingdom, the response identifying of human some distinctive NMJs to diseasefeature of processes. human NMJs, In the and final section,consider I consider how those what features is currently may influence known, the but response mostly not of human known, NMJs about to the disease molecular processes. basis In of the these functionallyfinal section, significant I consider structuralwhat is currently features. known, The but references mostly not cited known, in this about review the molecular are a representative basis of sample,these functionally rather than asignificant comprehensive structural catalog features. of all published The references work of cited relevance. in this review are a representative sample, rather than a comprehensive catalog of all published work of relevance. 2. Basic Properties of the NMJ 2. Basic Properties of the NMJ 2.1. NMJ Structure 2.1. NMJ Structure The axons that control skeletal muscle cells arise from the centrally located cell bodies of the motorThe neurons axons and that travel, control generally skeletal unbranched,muscle cells arise to the from target the muscles. centrally There located they cell branch bodies profusely,of the andmotor make neurons contact and with travel, many generally muscle unbranched, fibers. The sitesto the of target nerve–muscle muscles. There contact they are branch highly profusely, specialized (Figureand make1). The contact fine (0.1with µmanym) motor muscle nerve fibers. terminal The site formss of nerve–muscle numerous varicosities contact are (“boutons”),highly specialized usually (Figure 1). The fine (0.1 μm) motor nerve terminal forms numerous varicosities (“boutons”), usually 1–5 µm across, from which transmitter is released (Figure1B). As revealed by electron microscopy, 1–5 μm across, from which transmitter is released (Figure 1B). As revealed by electron microscopy, in addition to many mitochondria and arrays of endoplasmic reticulum, the nerve terminal contains in addition to many mitochondria and arrays of endoplasmic reticulum, the nerve terminal contains many 50 nm diameter, membrane-bound synaptic vesicles (SVs) which contain the transmitter. The SVs many 50 nm diameter, membrane-bound synaptic vesicles (SVs) which contain the transmitter. The are normally particularly concentered around electron-dense structures in the presynaptic membrane, SVs are normally particularly concentered around electron-dense structures in the presynaptic knownmembrane, as the known “active as zones”, the “active which zones”, are the which sites are of evokethe sites transmitter of evoke transmitter release (Figure release1C). (Figure The boutons 1C). adhereThe boutons to the muscleadhere to cell the surface, muscle leavingcell surface, a gap leaving of about a gap 50–100 of about nm which50–100 containsnm which extracellular contains matrix,extracellular often taking matrix, the often form taking of a the discrete form of basal a disc laminarete basal (BL). lamina They (BL). are capped They are by capped several by non-neural several Schwannnon-neural cells. Schwann cells. FigureFigure 1. 1.Mammalian Mammalian neuromuscularneuromuscular junctions junctions (NMJ) (NMJ) structure. structure. (A (A) Diagram) Diagram showing showing a motor a motor axon axon whichwhich branches branches to to innervate innervate two two muscle muscle fibers fibers at at the th NMJs.e NMJs. Note Note the the extensive extensiv branchinge branching of of the the motor motor axon terminal.axon terminal. Arrow showsArrow region shows where region nerve where has nerve been removed,has been revealingremoved, postsynaptic revealing postsynaptic folds (From folds Salpeter, 1986,(From with Salpeter, permission) 1986, with [2]; (Bpermission)) Human NMJ[2]; (B showing) Humanthe NMJ nerve showing terminal the nerve (green, terminal immunolabeling (green, ofimmunolabeling synaptophysin andof synaptophysin neurofilament and protein) neurofilament and the postsynapticprotein) and the acetylcholine postsynaptic receptors acetylcholine (AChRs) receptors (AChRs) (red, fluorescent tagged α-bungarotoxin). Note the swollen “boutons” of the nerve (red, fluorescent tagged α-bungarotoxin). Note the swollen “boutons” of the nerve terminal, from which terminal, from which transmitter is released. Scale bar, 20 μm; (C) Electron micrograph of a section transmitter is released. Scale bar, 20 µm; (C) Electron micrograph of a section through a single bouton. through a single bouton. Note the extensive infolding of the postsynaptic muscle fiber membrane. Note the extensive infolding of
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