Genetic and Molecular Mechanisms in Multiple Sclerosis

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 January 2024) | Viewed by 12824

Special Issue Editors

Laboratory of Genetics of Neurological Complex Disorders, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
Interests: multiple sclerosis; next-generation sequencing; genomics; neurological disorders; neuroinflammation; epigenetics
Laboratory of Genetics of Neurological Complex Disorders, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
Interests: multiple sclerosis; next-generation sequencing; genomics; neurological disorders; neuroinflammation; epigenetics

Special Issue Information

Dear Colleagues,

Multiple sclerosis is a chronic, progressive, disabling disorder of the central nervous system. It is a complex disease whose susceptibility involves genetic and environmental factors. In recent years, significant improvements have been made to unravel the genetic causes of multiple sclerosis, highlighting a complex polygenic architecture that affects both susceptibility and phenotypical expression of the disease. Nonetheless, the identified variants explain ~50% of the genetic predisposition to multiple sclerosis, while their functional mechanism has been identified only in a few cases. Recently, relevance has also been given to multiple comprehensive strategies, evaluating the interplay of multiple layers of information, including gene expression, epigenetics and gene–environment interactions.

In this Special Issue, we welcome original research articles, reviews and short communications aimed at better defining the genetic and molecular mechanisms involved in multiple sclerosis, covering susceptibility but also the relationship between genetics and the manifestation of the disease (including endophenotypes, disease activity, progression, response to treatment). Special attention will be given to innovative and comprehensive approaches that aim to fill the gap of the so-called “missing heritability”. Studies may include but are not limited to the analysis of DNA sequencing data, investigation of rare variants, evaluation of the interaction between genetics and epigenetics, transcriptome and environment, as well as functional studies of putative relevant genes.

Dr. Melissa Sorosina
Dr. Silvia Santoro
Guest Editors

Manuscript Submission Information

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Keywords

  • multiple sclerosis
  • neuroinflammation
  • genomics
  • epigenetics
  • functional studies

Published Papers (6 papers)

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Research

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14 pages, 6195 KiB  
Communication
Integrating Rehabilomics into the Multi-Omics Approach in the Management of Multiple Sclerosis: The Way for Precision Medicine?
by Bruno Bonnechère
Genes 2023, 14(1), 63; https://doi.org/10.3390/genes14010063 - 24 Dec 2022
Cited by 3 | Viewed by 1438
Abstract
Over recent years, significant improvements have been made in the understanding of (epi)genetics and neuropathophysiological mechanisms driving the different forms of multiple sclerosis (MS). For example, the role and importance of the bidirectional communications between the brain and the gut—also referred to as [...] Read more.
Over recent years, significant improvements have been made in the understanding of (epi)genetics and neuropathophysiological mechanisms driving the different forms of multiple sclerosis (MS). For example, the role and importance of the bidirectional communications between the brain and the gut—also referred to as the gut-brain axis—in the pathogenesis of MS is receiving increasing interest in recent years and is probably one of the most promising areas of research for the management of people with MS. However, despite these important advances, it must be noted that these data are not—yet—used in rehabilitation. Neurorehabilitation is a cornerstone of MS patient management, and there are many techniques available to clinicians and patients, including technology-supported rehabilitation. In this paper, we will discuss how new findings on the gut microbiome could help us to better understand how rehabilitation can improve motor and cognitive functions. We will also see how the data gathered during the rehabilitation can help to get a better diagnosis of the patients. Finally, we will discuss how these new techniques can better guide rehabilitation to lead to precision rehabilitation and ultimately increase the quality of patient care. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms in Multiple Sclerosis)
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22 pages, 4244 KiB  
Article
A Whole-Genome Sequencing Study Implicates GRAMD1B in Multiple Sclerosis Susceptibility
by Federica Esposito, Ana Maria Osiceanu, Melissa Sorosina, Linda Ottoboni, Bryan Bollman, Silvia Santoro, Barbara Bettegazzi, Andrea Zauli, Ferdinando Clarelli, Elisabetta Mascia, Andrea Calabria, Daniele Zacchetti, Ruggero Capra, Maurizio Ferrari, Paolo Provero, Dejan Lazarevic, Davide Cittaro, Paola Carrera, Nikolaos Patsopoulos, Daniela Toniolo, A Dessa Sadovnick, Gianvito Martino, Philip L. De Jager, Giancarlo Comi, Elia Stupka, Carles Vilariño-Güell, Laura Piccio and Filippo Martinelli Boneschiadd Show full author list remove Hide full author list
Genes 2022, 13(12), 2392; https://doi.org/10.3390/genes13122392 - 16 Dec 2022
Cited by 1 | Viewed by 2143
Abstract
While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a [...] Read more.
While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.S601P) variant in the GRAMD1B gene that is shared within MS cases and resides under a linkage peak (LOD: 2.194). Sequencing GRAMD1B in 91 familial MS cases revealed two additional rare missense and two splice-site variants, two of which (rs755488531 and rs769527838) were not found in 1000 Italian healthy controls. Functional studies demonstrated that GRAMD1B, a gene with unknown function in the central nervous system (CNS), is expressed by several cell types, including astrocytes, microglia and neurons as well as by peripheral monocytes and macrophages. Notably, GRAMD1B was downregulated in vessel-associated astrocytes of active MS lesions in autopsied brains and by inflammatory stimuli in peripheral monocytes, suggesting a possible role in the modulation of inflammatory response and disease pathophysiology. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms in Multiple Sclerosis)
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13 pages, 1560 KiB  
Article
TWEAK and TNFα, Both TNF Ligand Family Members and Multiple Sclerosis-Related Cytokines, Induce Distinct Gene Response in Human Brain Microvascular Endothelial Cells
by Delphine Stephan, Anais Roger, Jehanne Aghzadi, Sylvie Carmona, Christophe Picard, Jean-Philippe Dales and Sophie Desplat-Jégo
Genes 2022, 13(10), 1714; https://doi.org/10.3390/genes13101714 - 24 Sep 2022
Viewed by 1546
Abstract
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF ligand family involved in various diseases including brain inflammatory pathologies such as multiple sclerosis. It has been demonstrated that TWEAK can induce cerebrovascular permeability in an in vitro model [...] Read more.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the TNF ligand family involved in various diseases including brain inflammatory pathologies such as multiple sclerosis. It has been demonstrated that TWEAK can induce cerebrovascular permeability in an in vitro model of the blood–brain barrier. The molecular mechanisms playing a role in TWEAK versus TNFα signaling on cerebral microvascular endothelial cells are not well defined. Therefore, we aimed to identify gene expression changes in cultures of human brain microvascular endothelial cells (hCMEC/D3) to address changes initiated by TWEAK exposure. Taken together, our studies highlighted that gene involved in leukocyte extravasation, notably claudin-5, were differentially modulated by TWEAK and TNFα. We identified differential gene expression of hCMEC/D3 cells at three timepoints following TWEAK versus TNFα stimulation and also found distinct modulations of several canonical pathways including the actin cytoskeleton, vascular endothelial growth factor (VEGF), Rho family GTPases, and phosphatase and tensin homolog (PTEN) pathways. To our knowledge, this is the first study to interrogate and compare the effects of TWEAK versus TNFα on gene expression in brain microvascular endothelial cells. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms in Multiple Sclerosis)
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30 pages, 4002 KiB  
Article
Nrf2/HO-1 Signaling Stimulation through Acetyl-11-Keto-Beta-Boswellic Acid (AKBA) Provides Neuroprotection in Ethidium Bromide-Induced Experimental Model of Multiple Sclerosis
by Shubham Upadhayay, Sidharth Mehan, Aradhana Prajapati, Pranshul Sethi, Manisha Suri, Ayat Zawawi, Majed N. Almashjary and Shams Tabrez
Genes 2022, 13(8), 1324; https://doi.org/10.3390/genes13081324 - 25 Jul 2022
Cited by 16 | Viewed by 2685
Abstract
Multiple sclerosis (MS) is a severe immune-mediated neurological disease characterized by neuroinflammation, demyelination, and axonal degeneration in the central nervous system (CNS). This is frequently linked to motor abnormalities and cognitive impairments. The pathophysiological hallmarks of MS include inflammatory demyelination, axonal injury, white [...] Read more.
Multiple sclerosis (MS) is a severe immune-mediated neurological disease characterized by neuroinflammation, demyelination, and axonal degeneration in the central nervous system (CNS). This is frequently linked to motor abnormalities and cognitive impairments. The pathophysiological hallmarks of MS include inflammatory demyelination, axonal injury, white matter degeneration, and the development of CNS lesions that result in severe neuronal degeneration. Several studies suggested downregulation of nuclear factor erythroid-2-related factor-2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling is a causative factor for MS pathogenesis. Acetyl-11-keto-β-boswellic acid (AKBA) is an active pentacyclictriterpenoid obtained from Boswellia serrata, possessing antioxidant and anti-inflammatory properties. The present study explores the protective potential of AKBA on behavioral, molecular, neurochemical, and gross pathological abnormalitiesandhistopathological alterations by H&E and LFB staining techniques in an experimental model of multiple sclerosis, emphasizing the increase inNrf2/HO-1 levels in the brain. Moreover, we also examine the effect of AKBA on the intensity of myelin basic protein (MBP) in CSF and rat brain homogenate. Specific apoptotic markers (Bcl-2, Bax, andcaspase-3) were also estimated in rat brain homogenate. Neuro behavioralabnormalities in rats were examined using an actophotometer, rotarod test, beam crossing task (BCT),and Morris water maze (MWM). AKBA 50 mg/kg and 100 mg/kg were given orally from day 8 to 35 to alleviate MS symptoms in the EB-injected rats. Furthermore, cellular, molecular, neurotransmitter, neuroinflammatory cytokine, and oxidative stress markers in rat whole brain homogenate, blood plasma, and cerebral spinal fluid were investigated. This study shows that AKBA upregulates the level of antioxidant proteins such as Nrf2 and HO-1 in the rat brain. AKBA restores altered neurochemical levels, potentially preventing gross pathological abnormalities during MS progression. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms in Multiple Sclerosis)
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8 pages, 235 KiB  
Article
Role of Multiple Vitamin D-Related Polymorphisms in Multiple Sclerosis Severity: Preliminary Findings
by Luisa Agnello, Concetta Scazzone, Bruna Lo Sasso, Matteo Vidali, Rosaria Vincenza Giglio, Anna Maria Ciaccio, Paolo Ragonese, Giuseppe Salemi and Marcello Ciaccio
Genes 2022, 13(8), 1307; https://doi.org/10.3390/genes13081307 - 22 Jul 2022
Viewed by 1818
Abstract
Background: Multiple Sclerosis (MS) is a multifactorial disease whose pathogenesis is the result of interaction among genetic, epigenetic, and environmental factors. Among these, a role for vitamin D hypovitaminosis has emerged in recent decades. Vitamin D levels are influenced by both environmental and [...] Read more.
Background: Multiple Sclerosis (MS) is a multifactorial disease whose pathogenesis is the result of interaction among genetic, epigenetic, and environmental factors. Among these, a role for vitamin D hypovitaminosis has emerged in recent decades. Vitamin D levels are influenced by both environmental and genetic factors. Single nucleotide polymorphisms (SNPs) in genes codifying for molecules involved in vitamin D metabolism have been associated with an increased risk of developing MS. However, few studies assessed the association of such SNPs with the severity of the disease. The aim of this observational study was to evaluate the potential association among vitamin D status, MS severity, and vitamin D-related SNPs, alone or in combination. Methods: In a cohort of 100 MS patients, we genotyped 18 SNPs in the following genes: NAD synthetase 1, CYP2R1, vitamin D binding protein, vitamin D receptor, Retinoid X Receptor-α, KLOTHO, CYP24A1, and CYP27A1. Serum 25(OH)D3 levels were measured by high-performance liquid chromatography. Genotyping was performed by real-time polymerase chain reaction or PCR-RFLP. Results: We did not find any association between SNPs, alone or in combination, and MS severity. Conclusion: In this study, we make an initial evaluation of the possible influence of several SNPs in vitamin D-related genes on MS severity. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms in Multiple Sclerosis)

Review

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29 pages, 946 KiB  
Review
The Role of Cytotoxic T-Lymphocyte Antigen 4 in the Pathogenesis of Multiple Sclerosis
by Maria Sofia Basile, Placido Bramanti and Emanuela Mazzon
Genes 2022, 13(8), 1319; https://doi.org/10.3390/genes13081319 - 24 Jul 2022
Cited by 2 | Viewed by 2272
Abstract
Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder of the central nervous system that presents heterogeneous clinical manifestations and course. It has been shown that different immune checkpoints, including Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), can be involved in the pathogenesis of MS. CTLA-4 [...] Read more.
Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder of the central nervous system that presents heterogeneous clinical manifestations and course. It has been shown that different immune checkpoints, including Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), can be involved in the pathogenesis of MS. CTLA-4 is a critical regulator of T-cell homeostasis and self-tolerance and represents a key inhibitor of autoimmunity. In this scopingreview, we resume the current preclinical and clinical studies investigating the role of CTLA-4 in MS with different approaches. While some of these studies assessed the expression levels of CTLA-4 on T cells by comparing MS patients with healthy controls, others focused on the evaluation of the effects of common MS therapies on CTLA-4 modulation or on the study of the CTLA-4 blockade or deficiency in experimental autoimmune encephalomyelitis models. Moreover, other studies in this field aimed to discover if the CTLA-4 gene might be involved in the predisposition to MS, whereas others evaluated the effects of treatment with CTLA4-Ig in MS. Although these results are of great interest, they are often conflicting. Therefore, further studies are needed to reveal the exact mechanisms underlying the action of a crucial immune checkpoint such as CTLA-4 in MS to identify novel immunotherapeutic strategies for MS patients. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms in Multiple Sclerosis)
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