Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology

Ohkawara, Bisei; Ito, Mikako; Ohno, Kinji

doi:10.3390/ijms22052455

Cited by 25 publications

(26 citation statements)

References 120 publications

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“…The agrin-Lrp4-MuSK signalling pathway is the primary mechanism for the formation of NMJs. 27 AGRN mutations in our study were located in the Kazal-like 4 and Laminin EGF-like 2 domains (patient 1) and EGFlike 2 and Laminin G-like 2 domains (patient 2). Kazal-like domains function as protease inhibitors, contributing to the maintenance of a long-lasting synaptic structure.…”

Section: Gmppbmentioning

confidence: 64%

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Clinicopathological‐genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre

Huang

Duan

et al. 2022

J Cellular Molecular Medi

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Congenital myasthenic syndrome (CMS) encompasses a heterogeneous group of inherited disorders affecting nerve transmission across the neuromuscular junction. 1 The incidence of CMS was estimated to be 1.8-22.2 per million; however, due to the complexity of the procedures that are used to obtain an accurate diagnosis, incidence rates are likely underestimated. [2][3][4][5][6] Currently, more than 30 proteins are known to be involved in various types of CMS. Generally, proteins related to CMS are located at the presynaptic, synaptic or postsynaptic region of the neuromuscular junction (NMJ), or they undergo abnormal glycosylation. Among them, mutations in CHRNE, RAPSN and COLQ are the most frequent, accounting for half of CMS cases in a large-scale analysis including 680 patients. 7 Mutations in CMS-related genes can be used to accurately diagnose CMS.Generally, CMS is characterized by fatigability or skeletal muscle weakness with an onset at birth to early childhood.Electromyographic findings of a decrease in repetitive nerve stimulation (RNS) and increased jitter on single-fibre electromyography (EMG) may support the diagnosis. 8 Genetic testing or whole-exome sequencing could establish a diagnosis of CMS and guide pharmacological treatment. For example, β2-receptor agonist therapy could

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Section: Gmppbmentioning

confidence: 64%

“…Agrin is secreted into the synaptic basal lamina by the nerve terminal. The agrin‐Lrp4‐MuSK signalling pathway is the primary mechanism for the formation of NMJs 27 . AGRN mutations in our study were located in the Kazal‐like 4 and Laminin EGF‐like 2 domains (patient 1) and EGF‐like 2 and Laminin G‐like 2 domains (patient 2).…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological‐genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre

Huang

Duan

et al. 2022

J Cellular Molecular Medi

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“…These connections provide the structural bases of brain functions. Synaptic structures are largely formed during the early development stage and precisely regulated by evolutionally conserved molecules and signaling pathways, among which is the well‐known Wnt signaling (Salinas & Zou, 2008; Farias et al , 2010; Dickins & Salinas, 2013; Zwamborn et al , 2018; Ohkawara et al , 2021; Teo & Salinas, 2021).…”

Section: Introductionmentioning

confidence: 99%

Gut neuroendocrine signaling regulates synaptic assembly in C. elegans

Shi

et al. 2022

EMBO Reports

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Synaptic connections are essential to build a functional brain. How synapses are formed during development is a fundamental question in neuroscience. Recent studies provided evidence that the gut plays an important role in neuronal development through processing signals derived from gut microbes or nutrients. Defects in gut–brain communication can lead to various neurological disorders. Although the roles of the gut in communicating signals from its internal environment to the brain are well known, it remains unclear whether the gut plays a genetically encoded role in neuronal development. Using C. elegans as a model, we uncover that a Wnt‐endocrine signaling pathway in the gut regulates synaptic development in the brain. A canonical Wnt signaling pathway promotes synapse formation through regulating the expression of the neuropeptides encoding gene nlp‐40 in the gut, which functions through the neuronally expressed GPCR/AEX‐2 receptor during development. Wnt‐NLP‐40‐AEX‐2 signaling likely acts to modulate neuronal activity. Our study reveals a genetic role of the gut in synaptic development and identifies a novel contribution of the gut–brain axis.

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“…Another synaptic extracellular matrix, glycoprotein Agrin ( AGRN ), aids in the aggregation of postsynaptic nicotinic acetylcholine receptors (AChR). AGRN is secreted from the nerve terminal of spinal motor neurons and binds to low-density lipoprotein receptor-related protein 4 (Lrp4) and muscle-specific receptor tyrosine kinase (MuSK) on the postsynaptic muscle membrane [ 4 ]. The agrin-Lrp4-MuSK signaling pathway is primarily involved in developing and maintaining neuromuscular junctions (NMJs) [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Unfolding of Novel Independent Missense Mutations in VAMP2 and AGRN and Their Collective Role in Global Developmental Delay: A Case Report

Heidarpour¹,

Singh²,

Caputo³

et al. 2022

Cureus

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Vesicle-associated membrane protein 2 ( VAMP2 ) and Agrin ( AGRN ) are crucial proteins in neurotransmission. VAMP2 is a vesicular protein that facilitates the exocytosis of neurotransmitters. At the same time, AGRN plays a critical role in the maintenance and function of neuromuscular junctions. Mutations in the signaling pathway of VAMP2 and AGRN impair proper signaling between the presynaptic and postsynaptic neurons, and can result in neurodevelopmental conditions known as global developmental delay (GDD). This study highlights a presentation of GDD in a patient with concurrent mutations in VAMP2 and AGRN . A three-year-old female child presented with GDD characterized by hypotonia, intellectual disability, and dysphagia. Physical exam exhibited signs of developmental delay and severe muscle weakness. EEG findings were suggestive of a hypsarrhythmia pattern. The ophthalmological evaluation showed partial optic atrophy bilaterally. Therapeutic interventions included Keppra and Topamax, which proved ineffective. The patient’s outcome was inconclusive as care was transferred to another facility. This case study reports the novel appearance of two concurrent mutations: p.Gln76Pro associated with VAMP2 and p.Gln970Glu associated with AGRN . Mutations in VAMP2 lead to a dysfunctional SNARE complex and inhibit exocytosis of neurotransmitters into the synaptic cleft. Mutations in AGRN impair the ability to form and activate postsynaptic nicotinic acetylcholine receptors. Improper signaling between presynaptic and postsynaptic neurons is an important determinant of GDD. We hope that accounting for this mutational pattern will contribute to understanding synapse assembly and help unravel the complex interplay of factors involved in the pathology of neuromuscular disorders and GDD.

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Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology

Cited by 25 publications

References 120 publications

Clinicopathological‐genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre

Clinicopathological‐genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre

Gut neuroendocrine signaling regulates synaptic assembly in C. elegans

Unfolding of Novel Independent Missense Mutations in VAMP2 and AGRN and Their Collective Role in Global Developmental Delay: A Case Report

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