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Neuromuscular Diseases: From Pathogenic Mechanisms to Therapy
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Neuromuscular Diseases: From Pathogenic Mechanisms to Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 16987

Special Issue Editor

Prof. Dr. Claire Legay

E-Mail Website
Guest Editor
Saints-Pères Paris Institute for the Neurosciences, Faculté des Sciences Fondamentales et Biomédicales, Université de Paris, Paris Descartes, CNRS UMR 8003, Paris, France
Interests: neuromuscular; skeletal muscle; neuromuscular junction

Special Issue Information

Dear Colleagues,

Neuromuscular diseases are disorders that affect the peripheral nervous system and, more specifically, the neuromuscular junction and the skeletal muscle, either directly or subsequently leading to muscle defects. They can be either congenitally acquired or inherited. The past decade has seen impressive developments in new treatments for neuromuscular diseases. This Special Issue aims to collect research papers and reviews on neuromuscular diseases, with topics ranging from pathogenic mechanisms to molecular studies of treatment, and is expected to benefit the research and therapeutic efforts of the scientific and medical neuromuscular communities.

We encourage the submission of both original research articles and topical reviews. Since our journal is focused on molecular sciences, pure clinical research does not fit within the scope of this Special Issue.

Prof. Dr. Claire Legay
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (6 papers)

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Research

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16 pages, 3201 KiB  
Article
Molecular Analysis of a Congenital Myasthenic Syndrome Due to a Pathogenic Variant Affecting the C-Terminus of ColQ
by Susie Barbeau, Fannie Semprez, Alexandre Dobbertin, Laurine Merriadec, Florine Roussange, Bruno Eymard, Damien Sternberg, Emmanuel Fournier, Hanice Karasoy, Cécile Martinat and Claire Legay
Int. J. Mol. Sci. 2023, 24(22), 16217; https://doi.org/10.3390/ijms242216217 - 11 Nov 2023
Viewed by 994
Abstract
Congenital Myasthenic Syndromes (CMSs) are rare inherited diseases of the neuromuscular junction characterized by muscle weakness. CMSs with acetylcholinesterase deficiency are due to pathogenic variants in COLQ, a collagen that anchors the enzyme at the synapse. The two COLQ N-terminal domains have been [...] Read more.
Congenital Myasthenic Syndromes (CMSs) are rare inherited diseases of the neuromuscular junction characterized by muscle weakness. CMSs with acetylcholinesterase deficiency are due to pathogenic variants in COLQ, a collagen that anchors the enzyme at the synapse. The two COLQ N-terminal domains have been characterized as being biochemical and functional. They are responsible for the structure of the protein in the triple helix and the association of COLQ with acetylcholinesterase. To deepen the analysis of the distal C-terminal peptide properties and understand the CMSs associated to pathogenic variants in this domain, we have analyzed the case of a 32 year old male patient bearing a homozygote splice site variant c.1281 C > T that changes the sequence of the last 28 aa in COLQ. Using COS cell and mouse muscle cell expression, we show that the COLQ variant does not impair the formation of the collagen triple helix in these cells, nor its association with acetylcholinesterase, and that the hetero-oligomers are secreted. However, the interaction of COLQ variant with LRP4, a signaling hub at the neuromuscular junction, is decreased by 44% as demonstrated by in vitro biochemical methods. In addition, an increase in all acetylcholine receptor subunit mRNA levels is observed in muscle cells derived from the patient iPSC. All these approaches point to pathophysiological mechanisms essentially characterized by a decrease in signaling and the presence of immature acetylcholine receptors. Full article
(This article belongs to the Special Issue Neuromuscular Diseases: From Pathogenic Mechanisms to Therapy)
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Review

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19 pages, 690 KiB  
Review
Unlocking the Complexity of Neuromuscular Diseases: Insights from Human Pluripotent Stem Cell-Derived Neuromuscular Junctions
by Morgan Gazzola and Cécile Martinat
Int. J. Mol. Sci. 2023, 24(20), 15291; https://doi.org/10.3390/ijms242015291 - 18 Oct 2023
Cited by 2 | Viewed by 1174
Abstract
Over the past 20 years, the use of pluripotent stem cells to mimic the complexities of the human neuromuscular junction has received much attention. Deciphering the key mechanisms underlying the establishment and maturation of this complex synapse has been driven by the dual [...] Read more.
Over the past 20 years, the use of pluripotent stem cells to mimic the complexities of the human neuromuscular junction has received much attention. Deciphering the key mechanisms underlying the establishment and maturation of this complex synapse has been driven by the dual goals of addressing developmental questions and gaining insight into neuromuscular disorders. This review aims to summarise the evolution and sophistication of in vitro neuromuscular junction models developed from the first differentiation of human embryonic stem cells into motor neurons to recent neuromuscular organoids. We also discuss the potential offered by these models to decipher different neuromuscular diseases characterised by defects in the presynaptic compartment, the neuromuscular junction, and the postsynaptic compartment. Finally, we discuss the emerging field that considers the use of these techniques in drug screening assay and the challenges they will face in the future. Full article
(This article belongs to the Special Issue Neuromuscular Diseases: From Pathogenic Mechanisms to Therapy)
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19 pages, 2518 KiB  
Review
Spinal Muscular Atrophy: An Evolving Scenario through New Perspectives in Diagnosis and Advances in Therapies
by Ilaria Angilletta, Rossella Ferrante, Roberta Giansante, Lucia Lombardi, Alessandra Babore, Anastasia Dell’Elice, Elisa Alessandrelli, Stefania Notarangelo, Marianna Ranaudo, Claudia Palmarini, Vincenzo De Laurenzi, Liborio Stuppia and Claudia Rossi
Int. J. Mol. Sci. 2023, 24(19), 14873; https://doi.org/10.3390/ijms241914873 - 3 Oct 2023
Viewed by 1919
Abstract
Spinal muscular atrophy (SMA) linked to 5q is a recessive motor neuron disease characterized by progressive and diffuse weakness and muscular atrophy. SMA is the most common neurodegenerative disease in childhood with an incidence of approximately 1 in 6000–10,000 live births, being long [...] Read more.
Spinal muscular atrophy (SMA) linked to 5q is a recessive motor neuron disease characterized by progressive and diffuse weakness and muscular atrophy. SMA is the most common neurodegenerative disease in childhood with an incidence of approximately 1 in 6000–10,000 live births, being long considered a leading cause of hereditary mortality in infancy, worldwide. The classification of SMA is based on the natural history of the disease, with a wide clinical spectrum of onset and severity. We are currently in a new therapeutic era, that, thanks to the widespread use of the newly approved disease-modifying therapies and the possibility of an early administration, should lead to a deep change in the clinical scenario and, thus, in the history of SMA. With the aim to achieve a new view of SMA, in this review we consider different aspects of this neuromuscular disease: the historical perspective, the clinical features, the diagnostic process, the psychological outcome, innovation in treatments and therapies, the possibility of an early identification of affected infants in the pre-symptomatic phase through newborn screening programs. Full article
(This article belongs to the Special Issue Neuromuscular Diseases: From Pathogenic Mechanisms to Therapy)
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20 pages, 1653 KiB  
Review
Mitochondrial Mutations Can Alter Neuromuscular Transmission in Congenital Myasthenic Syndrome and Mitochondrial Disease
by Kaela O’Connor, Sally Spendiff, Hanns Lochmüller and Rita Horvath
Int. J. Mol. Sci. 2023, 24(10), 8505; https://doi.org/10.3390/ijms24108505 - 9 May 2023
Cited by 1 | Viewed by 3172
Abstract
Congenital myasthenic syndromes (CMS) are a group of rare, neuromuscular disorders that usually present in childhood or infancy. While the phenotypic presentation of these disorders is diverse, the unifying feature is a pathomechanism that disrupts neuromuscular transmission. Recently, two mitochondrial genes—SLC25A1 and TEFM—have [...] Read more.
Congenital myasthenic syndromes (CMS) are a group of rare, neuromuscular disorders that usually present in childhood or infancy. While the phenotypic presentation of these disorders is diverse, the unifying feature is a pathomechanism that disrupts neuromuscular transmission. Recently, two mitochondrial genes—SLC25A1 and TEFM—have been reported in patients with suspected CMS, prompting a discussion about the role of mitochondria at the neuromuscular junction (NMJ). Mitochondrial disease and CMS can present with similar symptoms, and potentially one in four patients with mitochondrial myopathy exhibit NMJ defects. This review highlights research indicating the prominent roles of mitochondria at both the pre- and postsynapse, demonstrating the potential for mitochondrial involvement in neuromuscular transmission defects. We propose the establishment of a novel subcategorization for CMS—mitochondrial CMS, due to unifying clinical features and the potential for mitochondrial defects to impede transmission at the pre- and postsynapse. Finally, we highlight the potential of targeting the neuromuscular transmission in mitochondrial disease to improve patient outcomes. Full article
(This article belongs to the Special Issue Neuromuscular Diseases: From Pathogenic Mechanisms to Therapy)
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14 pages, 1728 KiB  
Review
APP in the Neuromuscular Junction for the Development of Sarcopenia and Alzheimer’s Disease
by Min-Yi Wu, Wen-Jun Zou, Daehoon Lee, Lin Mei and Wen-Cheng Xiong
Int. J. Mol. Sci. 2023, 24(9), 7809; https://doi.org/10.3390/ijms24097809 - 25 Apr 2023
Cited by 4 | Viewed by 2452
Abstract
Sarcopenia, an illness condition usually characterized by a loss of skeletal muscle mass and muscle strength or function, is often associated with neurodegenerative diseases, such as Alzheimer’s disease (AD), a common type of dementia, leading to memory loss and other cognitive impairment. However, [...] Read more.
Sarcopenia, an illness condition usually characterized by a loss of skeletal muscle mass and muscle strength or function, is often associated with neurodegenerative diseases, such as Alzheimer’s disease (AD), a common type of dementia, leading to memory loss and other cognitive impairment. However, the underlying mechanisms for their associations and relationships are less well understood. The App, a Mendelian gene for early-onset AD, encodes amyloid precursor protein (APP), a transmembrane protein enriched at both the neuromuscular junction (NMJ) and synapses in the central nervous system (CNS). Here, in this review, we highlight APP and its family members’ physiological functions and Swedish mutant APP (APPswe)’s pathological roles in muscles and NMJ. Understanding APP’s pathophysiological functions in muscles and NMJ is likely to uncover insights not only into neuromuscular diseases but also AD. We summarize key findings from the burgeoning literature, which may open new avenues to investigate the link between muscle cells and brain cells in the development and progression of AD and sarcopenia. Full article
(This article belongs to the Special Issue Neuromuscular Diseases: From Pathogenic Mechanisms to Therapy)
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48 pages, 3463 KiB  
Review
Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review
by Kinji Ohno, Bisei Ohkawara, Xin-Ming Shen, Duygu Selcen and Andrew G. Engel
Int. J. Mol. Sci. 2023, 24(4), 3730; https://doi.org/10.3390/ijms24043730 - 13 Feb 2023
Cited by 25 | Viewed by 6790
Abstract
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, [...] Read more.
Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles. Full article
(This article belongs to the Special Issue Neuromuscular Diseases: From Pathogenic Mechanisms to Therapy)
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