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Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies

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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 (30 April 2022) | Viewed by 37227

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Dr. Elisabetta Coppi

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Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, 50121 Florence, Italy
Interests: electrophysiology; patch clamp; synaptic transmission; long term potentiation; immunocytochemistry; oxygen glucose deprivation; myelin; oligodendrocytes; brain ischemia; multiple sclerosis; adenosine receptors
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Special Issue Information

Dear colleagues,

This Special Issue is dedicated to the study of multiple sclerosis (MS) and other demyelinating pathologies, and will publish a collection of original research or review articles related to this topic. Highlights in the field of neuroinflammation, myelin damage, immune-mediated responses in the central nervous system (CNS), and consequent neurological deficits will be discussed. Articles should debate how these mechanisms cause or contribute to the progression of neuroinflammation and associated myelin damage or neurological symptoms, and how they might represent innovative targets for future treatments. Studies that include animal models of demyelinating pathologies (i.e., the experimental autoimmune encephalomyelitis (EAE)), the investigation of glial cells and their different roles in the pathogenesis of demyelinating diseases, research based on in vitro models of oligodendroglial/astrocyte/microglial cell cultures or co-cultures of OPC/DRG neurons as in vitro assays of de-myelination/re-myelination are highly welcome, as is research on genetic polymorphisms or epigenetic mechanisms associated with MS.

Given your profound expertise in the field, it is my pleasure and honor to invite you to contribute to this Special Issue.

If you decide to accept, I would greatly appreciate if you could send me a tentative title and a 250-word abstract summarizing your work.

Dr. Elisabetta Coppi
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.

Keywords

demyelination
glia
oligodendrocyte differentiation
oligodendrocyte progenitor cells
experimental autoimmune encephalomyelitis
T cells
autoimmunity
neuroinflammation
remyelination
neurobehavioral deficit
macrophage/microglia with matter lesion

Related Special Issue

Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies 2.0 in International Journal of Molecular Sciences (4 articles)

Published Papers (11 papers)

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Research

Jump to: Review, Other

16 pages, 3515 KiB

Open AccessArticle

Immunogenicity of the Envelope Surface Unit of Human Endogenous Retrovirus K18 in Mice

by Victoria Ilse, Rebekka Scholz, Michael Wermann, Marcel Naumann, Martin S. Staege, Steffen Roßner and Holger Cynis

Int. J. Mol. Sci. 2022, 23(15), 8330; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158330 - 28 Jul 2022

Cited by 1 | Viewed by 1768

Abstract

The triggers for the development of multiple sclerosis (MS) have not been fully understood to date. One hypothesis proposes a viral etiology. Interestingly, viral proteins from human endogenous retroviruses (HERVs) may play a role in the pathogenesis of MS. Allelic variants of the HERV-K18 env gene represent a genetic risk factor for MS, and the envelope protein is considered to be an Epstein–Barr virus-trans-activated superantigen. To further specify a possible role for HERV-K18 in MS, the present study examined the immunogenicity of the purified surface unit (SU). HERV-K18(SU) induced envelope-specific plasma IgG in immunized mice and triggered proliferation of T cells isolated from these mice. It did not trigger phenotypic changes in a mouse model of experimental autoimmune encephalomyelitis. Further studies are needed to investigate the underlying mechanisms of HERV-K18 interaction with immune system regulators in more detail. Full article

(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)

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14 pages, 977 KiB

Open AccessArticle

Platelet Inhibition by Low-Dose Acetylsalicylic Acid Reduces Neuroinflammation in an Animal Model of Multiple Sclerosis

by Anna Vogelsang, Susann Eichler, Niklas Huntemann, Lars Masanneck, Hannes Böhnlein, Lisa Schüngel, Alice Willison, Karin Loser, Bernhard Nieswandt, Beate E. Kehrel, Alexander Zarbock, Kerstin Göbel and Sven G. Meuth

Int. J. Mol. Sci. 2021, 22(18), 9915; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189915 - 14 Sep 2021

Cited by 7 | Viewed by 2106

Abstract

Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4⁺ T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28% in ASA-treated mice compared to 56.11 ± 1.46% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A₂ were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS. Full article

(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)

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15 pages, 25125 KiB

Open AccessArticle

Teriflunomide Inhibits JCPyV Infection and Spread in Glial Cells and Choroid Plexus Epithelial Cells

by Bethany A. O’Hara, Gretchen V. Gee, Sheila A. Haley, Jenna Morris-Love, Charlotte Nyblade, Chris Nieves, Barbara A. Hanson, Xin Dang, Timothy J. Turner, Jeffrey M. Chavin, Alex Lublin, Igor J. Koralnik and Walter J. Atwood

Int. J. Mol. Sci. 2021, 22(18), 9809; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189809 - 10 Sep 2021

Cited by 6 | Viewed by 2795

Abstract

Several classes of immunomodulators are used for treating relapsing-remitting multiple sclerosis (RRMS). Most of these disease-modifying therapies, except teriflunomide, carry the risk of progressive multifocal leukoencephalopathy (PML), a severely debilitating, often fatal virus-induced demyelinating disease. Because teriflunomide has been shown to have antiviral activity against DNA viruses, we investigated whether treatment of cells with teriflunomide inhibits infection and spread of JC polyomavirus (JCPyV), the causative agent of PML. Treatment of choroid plexus epithelial cells and astrocytes with teriflunomide reduced JCPyV infection and spread. We also used droplet digital PCR to quantify JCPyV DNA associated with extracellular vesicles isolated from RRMS patients. We detected JCPyV DNA in all patients with confirmed PML diagnosis (n = 2), and in six natalizumab-treated (n = 12), two teriflunomide-treated (n = 7), and two nonimmunomodulated (n = 2) patients. Of the 21 patients, 12 (57%) had detectable JCPyV in either plasma or serum. CSF was uniformly negative for JCPyV. Isolation of extracellular vesicles did not increase the level of detection of JCPyV DNA versus bulk unprocessed biofluid. Overall, our study demonstrated an effect of teriflunomide inhibiting JCPyV infection and spread in glial and choroid plexus epithelial cells. Larger studies using patient samples are needed to correlate these in vitro findings with patient data. Full article

(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)

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16 pages, 3509 KiB

Open AccessArticle

Transcranial Magnetic Stimulation Improves Muscle Involvement in Experimental Autoimmune Encephalomyelitis

by Maria Angeles Peña-Toledo, Evelio Luque, Ignacio Ruz-Caracuel, Eduardo Agüera, Ignacio Jimena, Jose Peña-Amaro and Isaac Tunez

Int. J. Mol. Sci. 2021, 22(16), 8589; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168589 - 10 Aug 2021

Cited by 2 | Viewed by 2527

Abstract

Skeletal muscle is affected in experimental autoimmune encephalomyelitis (EAE), which is a model of multiple sclerosis that produces changes including muscle atrophy; histological features of neurogenic involvement, and increased oxidative stress. In this study, we aimed to evaluate the therapeutic effects of transcranial magnetic stimulation (TMS) on the involvement of rat skeletal muscle and to compare them with those produced by natalizumab (NTZ). EAE was induced by injecting myelin oligodendrocyte glycoprotein (MOG) into Dark Agouti rats. Both treatments, NTZ and TMS, were implemented from day 15 to day 35. Clinical severity was studied, and after sacrifice, the soleus and extensor digitorum longus muscles were extracted for subsequent histological and biochemical analysis. The treatment with TMS and NTZ had a beneficial effect on muscle involvement in the EAE model. There was a clinical improvement in functional motor deficits, atrophy was attenuated, neurogenic muscle lesions were reduced, and the level of oxidative stress biomarkers was lower in both treatment groups. Compared to NTZ, the best response was obtained with TMS for all the parameters analyzed. The myoprotective effect of TMS was higher than that of NTZ. Thus, the use of TMS may be an effective strategy to reduce muscle involvement in multiple sclerosis. Full article

(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)

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15 pages, 3056 KiB

Open AccessArticle

The Distribution of GPR17-Expressing Cells Correlates with White Matter Inflammation Status in Brain Tissues of Multiple Sclerosis Patients

by Jacopo Angelini, Davide Marangon, Stefano Raffaele, Davide Lecca and Maria P. Abbracchio

Int. J. Mol. Sci. 2021, 22(9), 4574; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094574 - 27 Apr 2021

Cited by 12 | Viewed by 3850

Abstract

In multiple sclerosis (MS), oligodendrocyte precursor cells (OPCs) are recruited to the site of injury to remyelinate damaged axons; however, in patients this process is often ineffective due to defects in OPC maturation. The membrane receptor GPR17 timely regulates the early stages of OPC differentiation; however, after reaching its highest levels in immature oligodendrocytes, it has to be downregulated to allow terminal maturation. Since, in several animal models of disease GPR17 is upregulated, the aim of this work was to characterize GPR17 alterations in MS patients. We developed immunohistochemistry and immunofluorescence procedures for the detection of GPR17 in human tissues and stained post-mortem MS brain lesions from patients with secondary progressive MS and control subjects. The inflammatory activity in each lesion was evaluated by immunohistochemistry for the myelin protein MOG and the HLA antigen to classify them as active, chronic inactive or chronic active. Hence, we assessed the distribution of GPR17-positive cells in these lesions compared to normal appearing white matter (NAWM) and white matter (WM) of control subjects. Our data have shown a marked increase of GPR17-expressing oligodendroglial cells accumulating at NAWM, in which moderate inflammation was also found. Furthermore, we identified two distinct subpopulations of GPR17-expressing oligodendroglial cells, characterized by either ramified or rounded morphology, that differently populate the WM of healthy controls and MS patients. We concluded that the coordinated presence of GPR17 in OPCs at the lesion sites and inflamed NAWM areas suggests that GPR17 could be exploited to support endogenous remyelination through advanced pharmacological approaches. Full article

(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)

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Review

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12 pages, 313 KiB

Open AccessReview

Targeting the RNA-Binding Protein HuR as Potential Thera-Peutic Approach for Neurological Disorders: Focus on Amyo-Trophic Lateral Sclerosis (ALS), Spinal Muscle Atrophy (SMA) and Multiple Sclerosis

by Vittoria Borgonetti, Elisabetta Coppi and Nicoletta Galeotti

Int. J. Mol. Sci. 2021, 22(19), 10394; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910394 - 27 Sep 2021

Cited by 4 | Viewed by 2420

Abstract

The importance of precise co- and post-transcriptional processing of RNA in the regulation of gene expression has become increasingly clear. RNA-binding proteins (RBPs) are a class of proteins that bind single- or double-chain RNA, with different affinities and selectivity, thus regulating the various functions of RNA and the fate of the cells themselves. ELAV (embryonic lethal/abnormal visual system)/Hu proteins represent an important family of RBPs and play a key role in the fate of newly transcribed mRNA. ELAV proteins bind AU-rich element (ARE)-containing transcripts, which are usually present on the mRNA of proteins such as cytokines, growth factors, and other proteins involved in neuronal differentiation and maintenance. In this review, we focused on a member of ELAV/Hu proteins, HuR, and its role in the development of neurodegenerative disorders, with a particular focus on demyelinating diseases. Full article

(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)

23 pages, 820 KiB

Open AccessReview

Potential Biomarkers Associated with Multiple Sclerosis Pathology

by Deepali Mathur, Bikash Kumar Mishra, Soumyashree Rout, Francisco Jose Lopez-Iranzo, Gerardo Lopez-Rodas, Jayalakshmi Vallamkondu, Ramesh Kandimalla and Bonaventura Casanova

Int. J. Mol. Sci. 2021, 22(19), 10323; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910323 - 25 Sep 2021

Cited by 13 | Viewed by 3709

Abstract

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS) that involves an intricate and aberrant interaction of immune cells leading to inflammation, demyelination, and neurodegeneration. Due to the heterogeneity of clinical subtypes, their diagnosis becomes challenging and the best treatment cannot be easily provided to patients. Biomarkers have been used to simplify the diagnosis and prognosis of MS, as well as to evaluate the results of clinical treatments. In recent years, research on biomarkers has advanced rapidly due to their ability to be easily and promptly measured, their specificity, and their reproducibility. Biomarkers are classified into several categories depending on whether they address personal or predictive susceptibility, diagnosis, prognosis, disease activity, or response to treatment in different clinical courses of MS. The identified members indicate a variety of pathological processes of MS, such as neuroaxonal damage, gliosis, demyelination, progression of disability, and remyelination, among others. The present review analyzes biomarkers in cerebrospinal fluid (CSF) and blood serum, the most promising imaging biomarkers used in clinical practice. Furthermore, it aims to shed light on the criteria and challenges that a biomarker must face to be considered as a standard in daily clinical practice. Full article

(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)

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18 pages, 1554 KiB

Open AccessReview

Myelin Defects in Niemann–Pick Type C Disease: Mechanisms and Possible Therapeutic Perspectives

by Antonietta Bernardo, Chiara De Nuccio, Sergio Visentin, Alberto Martire, Luisa Minghetti, Patrizia Popoli and Antonella Ferrante

Int. J. Mol. Sci. 2021, 22(16), 8858; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168858 - 17 Aug 2021

Cited by 11 | Viewed by 3710

Abstract

Niemann–Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, NPC1 and NPC2, coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane. The first trait of NPC is the accumulation of unesterified cholesterol and other lipids, like sphingosine and glycosphingolipids, in the late endosomal and lysosomal compartments, which causes the blockade of autophagic flux and the impairment of mitochondrial functions. In the brain, the main consequences of NPC are cerebellar neurodegeneration, neuroinflammation, and myelin defects. This review will focus on myelin defects and the pivotal importance of cholesterol for myelination and will offer an overview of the molecular targets and the pharmacological strategies so far proposed, or an object of clinical trials for NPC. Finally, it will summarize recent data on a new and promising pharmacological perspective involving A_2A adenosine receptor stimulation in genetic and pharmacological NPC dysmyelination models. Full article

(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)

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44 pages, 1353 KiB

Open AccessReview

Proteomics of Multiple Sclerosis: Inherent Issues in Defining the Pathoetiology and Identifying (Early) Biomarkers

by Monokesh K. Sen, Mohammed S. M. Almuslehi, Peter J. Shortland, David A. Mahns and Jens R. Coorssen

Int. J. Mol. Sci. 2021, 22(14), 7377; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147377 - 09 Jul 2021

Cited by 11 | Viewed by 3722

Abstract

Multiple Sclerosis (MS) is a demyelinating disease of the human central nervous system having an unconfirmed pathoetiology. Although animal models are used to mimic the pathology and clinical symptoms, no single model successfully replicates the full complexity of MS from its initial clinical identification through disease progression. Most importantly, a lack of preclinical biomarkers is hampering the earliest possible diagnosis and treatment. Notably, the development of rationally targeted therapeutics enabling pre-emptive treatment to halt the disease is also delayed without such biomarkers. Using literature mining and bioinformatic analyses, this review assessed the available proteomic studies of MS patients and animal models to discern (1) whether the models effectively mimic MS; and (2) whether reasonable biomarker candidates have been identified. The implication and necessity of assessing proteoforms and the critical importance of this to identifying rational biomarkers are discussed. Moreover, the challenges of using different proteomic analytical approaches and biological samples are also addressed. Full article

(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)

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25 pages, 2046 KiB

Open AccessReview

Ion Channels as New Attractive Targets to Improve Re-Myelination Processes in the Brain

by Federica Cherchi, Irene Bulli, Martina Venturini, Anna Maria Pugliese and Elisabetta Coppi

Int. J. Mol. Sci. 2021, 22(14), 7277; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147277 - 06 Jul 2021

Cited by 12 | Viewed by 4074

Abstract

Multiple sclerosis (MS) is the most demyelinating disease of the central nervous system (CNS) characterized by neuroinflammation. Oligodendrocyte progenitor cells (OPCs) are cycling cells in the developing and adult CNS that, under demyelinating conditions, migrate to the site of lesions and differentiate into mature oligodendrocytes to remyelinate damaged axons. However, this process fails during disease chronicization due to impaired OPC differentiation. Moreover, OPCs are crucial players in neuro-glial communication as they receive synaptic inputs from neurons and express ion channels and neurotransmitter/neuromodulator receptors that control their maturation. Ion channels are recognized as attractive therapeutic targets, and indeed ligand-gated and voltage-gated channels can both be found among the top five pharmaceutical target groups of FDA-approved agents. Their modulation ameliorates some of the symptoms of MS and improves the outcome of related animal models. However, the exact mechanism of action of ion-channel targeting compounds is often still unclear due to the wide expression of these channels on neurons, glia, and infiltrating immune cells. The present review summarizes recent findings in the field to get further insights into physio-pathophysiological processes and possible therapeutic mechanisms of drug actions. Full article

(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)

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Other

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11 pages, 1199 KiB

Open AccessOpinion

Dopaminergic Receptor Targeting in Multiple Sclerosis: Is There Therapeutic Potential?

by Mikhail Melnikov, Mikhail Pashenkov and Alexey Boyko

Int. J. Mol. Sci. 2021, 22(10), 5313; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105313 - 18 May 2021

Cited by 13 | Viewed by 5048

Abstract

Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of dopamine on the cells of innate and adaptive immune systems, including Th17 cells, which play a critical role in inflammatory diseases of the CNS. This article reviews the literature data on the role of dopamine in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of dopaminergic receptor targeting on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of dopaminergic drugs as add-on pathogenetic therapy of MS, is discussed. Full article

(This article belongs to the Special Issue Multiple Sclerosis and Demyelinating Pathologies: Mechanisms and Cutting-Edge Therapies)

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