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Cell Reports Nov 2017The neuromuscular junction (NMJ) plays a fundamental role in transferring information from lower motor neuron to skeletal muscle to generate movement. It is also an...
The neuromuscular junction (NMJ) plays a fundamental role in transferring information from lower motor neuron to skeletal muscle to generate movement. It is also an experimentally accessible model synapse routinely studied in animal models to explore fundamental aspects of synaptic form and function. Here, we combined morphological techniques, super-resolution imaging, and proteomic profiling to reveal the detailed cellular and molecular architecture of the human NMJ. Human NMJs were significantly smaller, less complex, and more fragmented than mouse NMJs. In contrast to mice, human NMJs were also remarkably stable across the entire adult lifespan, showing no signs of age-related degeneration or remodeling. Super-resolution imaging and proteomic profiling revealed distinctive distribution of active zone proteins and differential expression of core synaptic proteins and molecular pathways at the human NMJ. Taken together, these findings reveal human-specific cellular and molecular features of the NMJ that distinguish them from comparable synapses in other mammalian species.
Topics: Aging; Animals; Humans; Motor Neurons; Muscle, Skeletal; Nervous System; Neuromuscular Junction; Proteomics; Synapses; Synaptic Transmission
PubMed: 29186674
DOI: 10.1016/j.celrep.2017.11.008 -
Translational Neurodegeneration Dec 2022Amyotrophic lateral sclerosis (ALS) is a disease characterized by upper and lower motor neuron (MN) loss with a signature feature of cytoplasmic aggregates containing... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a disease characterized by upper and lower motor neuron (MN) loss with a signature feature of cytoplasmic aggregates containing TDP-43, which are detected in nearly all patients. Mutations in the gene that encodes TDP-43 (TARBDP) are known to result in both familial and sporadic ALS. In ALS, disruption of neuromuscular junctions (NMJs) constitutes a critical event in disease pathogenesis, leading to denervation atrophy, motor impairments and disability. Morphological defects and impaired synaptic transmission at NMJs have been reported in several TDP-43 animal models and in vitro, linking TDP-43 dysregulation to the loss of NMJ integrity in ALS. Through the lens of the dying-back and dying-forward hypotheses of ALS, this review discusses the roles of TDP-43 related to synaptic function, with a focus on the potential molecular mechanisms occurring within MNs, skeletal muscles and glial cells that may contribute to NMJ disruption in ALS.
Topics: Animals; Amyotrophic Lateral Sclerosis; Neuromuscular Junction; Motor Neurons; Synaptic Transmission; DNA-Binding Proteins
PubMed: 36575535
DOI: 10.1186/s40035-022-00331-z -
Acta Neurobiologiae Experimentalis 2022Located between skeletal muscle fibers and motoneurons, the neuromuscular junction is a chemical synapse essential for the transmission of information from nervous...
Located between skeletal muscle fibers and motoneurons, the neuromuscular junction is a chemical synapse essential for the transmission of information from nervous system to skeletal muscle. There are many diseases related to neuromuscular junction dysfunction, including myasthenia gravis, Lambert‑Eaton myasthenic syndrome, congenital myasthenic syndromes, amyotrophic lateral sclerosis, and spinal muscular atrophy. The pathophysiological mechanisms of these diseases have been investigated using many animal models. Among them, mouse models are the most commonly used and have provided the majority of current data. Moreover, advances in human induced pluripotent stem cell technology has resulted in new opportunities to study neuromuscular junction disorders from both patients and healthy individuals. Currently, patient‑specific induced pluripotent stem cells derived from motor neurons have begun to be studied. These studies will help us achieve a more comprehensive understanding of diseases related to neuromuscular junction disorders. We will describe the research models of neuromuscular junction disorders and provide an overview of recent key findings.
Topics: Animals; Mice; Humans; Induced Pluripotent Stem Cells; Neuromuscular Junction; Neuromuscular Junction Diseases; Myasthenia Gravis; Models, Theoretical
PubMed: 36748973
DOI: 10.55782/ane-2022-048 -
Current Opinion in Clinical Nutrition... May 2016Denervation is a hallmark of age-related and other types of muscle wasting. This review focuses on recent insights and current viewpoints regarding the mechanisms and... (Review)
Review
PURPOSE OF REVIEW
Denervation is a hallmark of age-related and other types of muscle wasting. This review focuses on recent insights and current viewpoints regarding the mechanisms and clinical relevance of maintaining the neuromuscular junction to counteract muscle wasting resulting from aging or neural disease/damage.
RECENT FINDINGS
Activity-dependent regulation of autophagy, the agrin-muscle specific kinase-Lrp4 signaling axis, and sympathetic modulation are principal mechanisms involved in stabilizing the neuromuscular junction. These findings are derived from several animal models and were largely confirmed by human gene expression analysis as well as insights from rare neuromuscular diseases such as amyotrophic lateral sclerosis and congenital myasthenic syndromes. Based on these insights, agrin-derived fragments are currently being evaluated as biomarkers for age-related muscle wasting. Tuning of autophagy, of the agrin pathway, and of sympathetic input are being studied as clinical treatment of muscle wasting disorders.
SUMMARY
Basic research has revealed that maintenance of neuromuscular junctions and a few signaling pathways are important in the context of age-dependent and other forms of muscle wasting. These findings have recently started to enter clinical practice, but further research needs to substantiate and refine our knowledge.
Topics: Animals; Autophagy; Gene Expression Regulation; Humans; Models, Biological; Muscle Proteins; Muscular Atrophy; Nerve Degeneration; Nerve Tissue Proteins; Neuromuscular Junction; Neuromuscular Junction Diseases; Wasting Syndrome; Wnt Signaling Pathway
PubMed: 26870889
DOI: 10.1097/MCO.0000000000000267 -
Neurologic Clinics May 2018Neuromuscular junctions (NMJs) form between nerve terminals of spinal cord motor neurons and skeletal muscles, and perisynaptic Schwann cells and kranocytes cap NMJs.... (Review)
Review
Neuromuscular junctions (NMJs) form between nerve terminals of spinal cord motor neurons and skeletal muscles, and perisynaptic Schwann cells and kranocytes cap NMJs. One muscle fiber has one NMJ, which is innervated by one motor nerve terminal. NMJs are excitatory synapses that use P/Q-type voltage-gated calcium channels to release the neurotransmitter acetylcholine. Acetylcholine receptors accumulate at the postsynaptic specialization called the end plate on the muscle fiber membrane, the sarcolemma. Proteins essential for the organization of end plates include agrin secreted from nerve terminals, Lrp4 and MuSK receptors for agrin, and Dok-7 and rapsyn cytosolic proteins in the muscle.
Topics: Animals; Humans; Neuromuscular Junction
PubMed: 29655446
DOI: 10.1016/j.ncl.2018.01.009 -
Cellular and Molecular Life Sciences :... Mar 2015The neuromuscular junction (NMJ) is the synaptic connection between motor neurons and muscle fibers. It is involved in crucial processes such as body movements and... (Review)
Review
The neuromuscular junction (NMJ) is the synaptic connection between motor neurons and muscle fibers. It is involved in crucial processes such as body movements and breathing. Its proper development requires the guidance of motor axons toward their specific targets, the development of multi-innervated myofibers, and a selective synapse stabilization. It first consists of the removal of excessive motor axons on myofibers, going from multi-innervation to a single innervation of each myofiber. Whereas guidance cues of motor axons toward their specific muscular targets are well characterized, only few molecular and cellular cues have been reported as clues for selecting and stabilizing specific neuromuscular junctions. We will first provide a brief summary on NMJ development. We will then review molecular cues that are involved in NMJ stabilization, in both pre- and post-synaptic compartments, considering motor neurons and Schwann cells on the one hand, and muscle on the other hand. We will provide links with pathologies and highlight advances that can be brought both by basic research on NMJ development and clinical data resulting from the analyses of neurodegeneration of synaptic connections to obtain a better understanding of this process. The goal of this review is to highlight the findings toward understanding the roles of poly- or single-innervations and the underlying mechanisms of NMJ stabilization.
Topics: Animals; Axons; Humans; Motor Neurons; Muscles; Neuromuscular Junction; Synapses
PubMed: 25359233
DOI: 10.1007/s00018-014-1768-z -
Muscle & Nerve Oct 2021Recent development of novel therapies has improved mobility and quality of life for people suffering from inheritable neuromuscular disorders. Despite this progress, the... (Review)
Review
Recent development of novel therapies has improved mobility and quality of life for people suffering from inheritable neuromuscular disorders. Despite this progress, the majority of neuromuscular disorders are still incurable, in part due to a lack of predictive models of neuromuscular junction (NMJ) breakdown. Improvement of predictive models of a human NMJ would be transformative in terms of expanding our understanding of the mechanisms that underpin development, maintenance, and disease, and as a testbed with which to evaluate novel therapeutics. Induced pluripotent stem cells (iPSCs) are emerging as a clinically relevant and non-invasive cell source to create human NMJs to study synaptic development and maturation, as well as disease modeling and drug discovery. This review will highlight the recent advances and remaining challenges to generating an NMJ capable of eliciting contraction of stem cell-derived skeletal muscle in vitro. We explore the advantages and shortcomings of traditional NMJ culturing platforms, as well as the pioneering technologies and novel, biomimetic culturing systems currently in use to guide development and maturation of the neuromuscular synapse and extracellular microenvironment. Then, we will explore how this NMJ-in-a-dish can be used to study normal assembly and function of the efferent portion of the neuromuscular arc, and how neuromuscular disease-causing mutations disrupt structure, signaling, and function.
Topics: Animals; Humans; Induced Pluripotent Stem Cells; Lab-On-A-Chip Devices; Motor Neurons; Neuromuscular Junction; Stem Cells; Tissue Engineering
PubMed: 34328673
DOI: 10.1002/mus.27360 -
Neuroscience Letters Nov 2019In the early 1950s, Katz and his colleagues capitalized on the newly developed intracellular microelectrode recording technique to investigate synaptic transmission. For... (Review)
Review
In the early 1950s, Katz and his colleagues capitalized on the newly developed intracellular microelectrode recording technique to investigate synaptic transmission. For study they chose frog neuromuscular junction (NMJ), which was ideally suited due to the accessibility and large size of the muscle cells. Paradoxically, the large size precluded the use of next generation patch clamp technology. Consequently, electrophysiological study of synaptic function shifted to small central synapses made amenable by patch clamp. Recently, however, the unique features offered by zebrafish have rekindled interest in the NMJ as a model for electrophysiological study of synaptic transmission. The small muscle size and synaptic simplicity provide the singular opportunity to perform in vivo spinal motoneuron-target muscle patch clamp recordings. Additional incentive is provided by zebrafish lines harboring mutations in key synaptic proteins, many of which are embryonic lethal in mammals, but all of which are able to survive well past synapse maturation in zebrafish. This mini-review will highlight features that set zebrafish NMJs apart from traditional NMJs. We also draw into focus findings that offer the promise of identifying features that define release sites, which serve to set the upper limit of transmitter release. Since its conception several candidates representing release sites have been proposed, most of which are based on distinctions among vesicle pools in their state of readiness for release. However, models based on distinctions among vesicles have become enormously complicated and none adequately account for setting an upper limit for exocytosis in response to an action potential (AP). Specifically, findings from zebrafish NMJ point to an alternative model, positing that elements other than vesicles per se set the upper limits of release.
Topics: Animals; Long-Term Synaptic Depression; Neuromuscular Junction; Neurotransmitter Agents; Synaptic Transmission; Synaptic Vesicles; Zebrafish
PubMed: 31557523
DOI: 10.1016/j.neulet.2019.134503 -
Scientific Reports Mar 2022In needle electromyography, there are two spontaneous waveforms, miniature end plate potentials and "end plate spikes", appearing usually together. Miniature end plate...
In needle electromyography, there are two spontaneous waveforms, miniature end plate potentials and "end plate spikes", appearing usually together. Miniature end plate potentials are local, non-propagating postsynaptic waves, caused by spontaneous exocytosis of acetylcholine in the neuromuscular junction. The prevailing hypothesis states that "end plate spikes" are propagated postsynaptic action potentials of muscle fibers, caused by presynaptic irritation of the motor nerve or nerve terminal. Using several small concentric needle electrodes in parallel with the muscle fibers, most "end plate spikes" are strictly local or propagating for 2-4 mm. At the end plate zone, there are miniature end plate potentials without "end plate spikes". Local "end plate spikes" are junctional potentials of intrafusal gamma neuromuscular junctions of the nuclear bag fibers, and propagated "end plate spikes" are potentials of nuclear chain muscle fibers of muscle spindles. Miniature end plate potentials without "end plate spikes" at the end plate zone derive from alpha neuromuscular junctions. These findings contrast with the prevailing hypothesis. The history of observations and different hypotheses of the origin of end plate spikes are described.
Topics: Action Potentials; Electromyography; Motor Endplate; Muscle Spindles; Neuromuscular Junction
PubMed: 35273346
DOI: 10.1038/s41598-022-08239-4 -
EBioMedicine Nov 2020Duchenne muscular dystrophy (DMD) is the most common and relentless form of muscular dystrophy. The pleiotropic effects of dystrophin deficiency include remarkable... (Review)
Review
Duchenne muscular dystrophy (DMD) is the most common and relentless form of muscular dystrophy. The pleiotropic effects of dystrophin deficiency include remarkable impacts on neuromuscular junction (NMJ) structure and function. Some of these alterations contribute to the severe muscle wasting and weakness that distinguish DMD, while others attempt to compensate for them. Experimental approaches that correct NMJ biology in pre-clinical models of DMD attenuate disease progression and improve functional outcomes, which suggests that targeting the NMJ may be an effective therapeutic strategy for DMD patients. The objectives of this review are to 1) survey the distinctions in NMJ structure, function, and gene expression in the dystrophic context as compared to the healthy condition, and 2) summarize the efforts, opportunities and challenges to correct NMJ biology in DMD. This information will expand our basic understanding of neuromuscular biology and may be useful for designing novel NMJ-targeted drug or behavioural strategies to mitigate the dystrophic pathology and other disorders of the neuromuscular system.
Topics: Animals; Biomarkers; Disease Models, Animal; Disease Susceptibility; Dystrophin; Electrophysiological Phenomena; Gene Expression Regulation; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Molecular Targeted Therapy; Muscular Dystrophy, Duchenne; Mutation; Neuromuscular Junction; Phenotype; Signal Transduction
PubMed: 33039707
DOI: 10.1016/j.ebiom.2020.103032