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multiple sclerosis epigenetic

N K Singhal, H Huang, S Li, R Clements, J Gadd, A Daniels, E E Kooijman, P Bannerman, T Burns, F Guo, D Pleasure, E Freeman, L Shriver, J McDonough
The neuronal mitochondrial metabolite N-acetylaspartate (NAA) is decreased in the multiple sclerosis (MS) brain. NAA is synthesized in neurons by the enzyme N-acetyltransferase-8-like (NAT8L) and broken down in oligodendrocytes by aspartoacylase (ASPA) into acetate and aspartate. We have hypothesized that NAA links the metabolism of axons with oligodendrocytes to support myelination. To test this hypothesis, we performed lipidomic analyses using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance thin-layer chromatography (HPTLC) to identify changes in myelin lipid composition in postmortem MS brains and in NAT8L knockout (NAT8L(-/-)) mice which do not synthesize NAA...
October 5, 2016: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
Davide Lecca, Davide Marangon, Giusy T Coppolino, Aida Menéndez Méndez, Annamaria Finardi, Gloria Dalla Costa, Vittorio Martinelli, Roberto Furlan, Maria P Abbracchio
In the mature central nervous system (CNS), oligodendrocytes provide support and insulation to axons thanks to the production of a myelin sheath. During their maturation to myelinating cells, oligodendroglial precursors (OPCs) follow a very precise differentiation program, which is finely orchestrated by transcription factors, epigenetic factors and microRNAs (miRNAs), a class of small non-coding RNAs involved in post-transcriptional regulation. Any alterations in this program can potentially contribute to dysregulated myelination, impaired remyelination and neurodegenerative conditions, as it happens in multiple sclerosis (MS)...
October 4, 2016: Scientific Reports
Omkaram Gangisetty, Sengottuvelan Murugan
Epigenetic modifications, including DNA methylation, covalent histone modifications, and small noncoding RNAs, play a key role in regulating the gene expression. This regulatory mechanism is important in cellular differentiation and development. Recent advances in the field of epigenetics extended the role of epigenetic mechanisms in controlling key biological processes such as genome imprinting and X-chromosome inactivation. Aberrant epigenetic modifications are associated with the development of many diseases...
2016: Advances in Neurobiology
Maria Sokratous, Efthimios Dardiotis, Zisis Tsouris, Eleni Bellou, Amalia Michalopoulou, Vasileios Siokas, Stylianos Arseniou, Tzeni Stamati, Georgios Tsivgoulis, Dimitrios Bogdanos, Georgios M Hadjigeorgiou
Multiple sclerosis (MS) is an autoimmune inflammatory and neurodegenerative disease of the central nervous system that involves several not yet fully elucidated pathophysiologic mechanisms. There is increasing evidence that epigenetic modifications at level of DNA bases, histones, and micro-RNAs may confer risk for MS. DNA methylation seems to have a prominent role in the epigenetics of MS, as aberrant methylation in the promoter regions across genome may underlie several processes involved in the initiation and development of MS...
December 2016: Auto- Immunity Highlights
Emmanuelle Waubant, Anne-Louise Ponsonby, Maura Pugliatti, Heather Hanwell, Ellen M Mowry, Rogier Q Hintzen
The onset of multiple sclerosis (MS) occurs in childhood in about 5% of all patients with MS. The disease in adults has a complex genetic and environmental inheritability. One of the main risk factors, also confirmed in pediatric MS, is HLA DRB1*1501 In addition to genetic factors, a large part of disease susceptibility in adults is conferred by environmental risk factors such as low vitamin D status, exposure to cigarette smoking, and remote Epstein-Barr virus (EBV) infection. In children, both exposure to cigarette smoking and prior EBV infection have been reported consistently as risk factors for MS...
August 30, 2016: Neurology
Till F M Andlauer, Dorothea Buck, Gisela Antony, Antonios Bayas, Lukas Bechmann, Achim Berthele, Andrew Chan, Christiane Gasperi, Ralf Gold, Christiane Graetz, Jürgen Haas, Michael Hecker, Carmen Infante-Duarte, Matthias Knop, Tania Kümpfel, Volker Limmroth, Ralf A Linker, Verena Loleit, Felix Luessi, Sven G Meuth, Mark Mühlau, Sandra Nischwitz, Friedemann Paul, Michael Pütz, Tobias Ruck, Anke Salmen, Martin Stangel, Jan-Patrick Stellmann, Klarissa H Stürner, Björn Tackenberg, Florian Then Bergh, Hayrettin Tumani, Clemens Warnke, Frank Weber, Heinz Wiendl, Brigitte Wildemann, Uwe K Zettl, Ulf Ziemann, Frauke Zipp, Janine Arloth, Peter Weber, Milena Radivojkov-Blagojevic, Markus O Scheinhardt, Theresa Dankowski, Thomas Bettecken, Peter Lichtner, Darina Czamara, Tania Carrillo-Roa, Elisabeth B Binder, Klaus Berger, Lars Bertram, Andre Franke, Christian Gieger, Stefan Herms, Georg Homuth, Marcus Ising, Karl-Heinz Jöckel, Tim Kacprowski, Stefan Kloiber, Matthias Laudes, Wolfgang Lieb, Christina M Lill, Susanne Lucae, Thomas Meitinger, Susanne Moebus, Martina Müller-Nurasyid, Markus M Nöthen, Astrid Petersmann, Rajesh Rawal, Ulf Schminke, Konstantin Strauch, Henry Völzke, Melanie Waldenberger, Jürgen Wellmann, Eleonora Porcu, Antonella Mulas, Maristella Pitzalis, Carlo Sidore, Ilenia Zara, Francesco Cucca, Magdalena Zoledziewska, Andreas Ziegler, Bernhard Hemmer, Bertram Müller-Myhsok
We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation...
June 2016: Science Advances
Saeed Aslani, Naser Jafari, Mohammad Reza Javan, Jafar Karami, Majid Ahmadi, Mahmoud Jafarnejad
Breakthroughs in genetic studies, like whole human genome sequencing and genome-wide association studies (GWAS), have richened our knowledge of etiopathology of autoimmune diseases (AID) through discovery of genetic patterns. Nonetheless, the precise etiology of autoimmune diseases remains largely unknown. The lack of complete concordance of autoimmune disease in identical twins suggests that non-genetic factors also play a major role in determining disease susceptibility. Although there is no certain definition, epigenetics has been known as heritable alterations in gene function without changes in the nucleotide sequence...
July 6, 2016: Neuromolecular Medicine
Elena Ortona, Marina Pierdominici, Angela Maselli, Caterina Veroni, Francesca Aloisi, Yehuda Shoenfeld
Autoimmune diseases are characterized by an exaggerated immune response leading to damage and dysfunction of specific or multiple organs and tissues. Most autoimmune diseases are more prevalent in women than in men. Symptom severity, disease course, response to therapy and overall survival may also differ between males and females with autoimmune diseases. Sex hormones have a crucial role in this sex bias, with estrogens being potent stimulators of autoimmunity and androgens playing a protective role. Accumulating evidence indicates that genetic, epigenetic and environmental factors may also contribute to sex-related differences in risk and clinical course of autoimmune diseases...
April 2016: Annali Dell'Istituto Superiore di Sanità
Xiang Li, Bing Xiao, Xing-Shu Chen
Multiple sclerosis (MS) is a neurological and chronic inflammatory disease that is mediated by demyelination and axonal degeneration in the central nervous system (CNS). Studies have shown that immune system components such as CD4+, CD8+, CD44+ T cells, B lymphatic cells, and inflammatory cytokines play a critical role in inflammatory processes and myelin damage associated with MS. Nevertheless, the pathogenesis of MS remains poorly defined. DNA methylation, a significant epigenetic modification, is reported to be extensively involved in MS pathogenesis through the regulation of gene expression...
June 17, 2016: Molecular Neurobiology
Teresa Maria Creanza, Maria Liguori, Sabino Liuni, Nicoletta Nuzziello, Nicola Ancona
Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We re-analyzed 595 mRNA arrays from publicly available datasets by studying changes in gene co-expression networks in MS and in response to interferon (IFN)-β treatment...
2016: International Journal of Molecular Sciences
Veronique V Belzil, Rebecca B Katzman, Leonard Petrucelli
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two fatal neurodegenerative diseases seen in comorbidity in up to 50 % of cases. Despite tremendous efforts over the last two decades, no biomarkers or effective therapeutics have been identified to prevent, decelerate, or stop neuronal death in patients. While the identification of multiple mutations in more than two dozen genes elucidated the involvement of several mechanisms in the pathogenesis of both diseases, identifying the hexanucleotide repeat expansion in C9orf72, the most common genetic abnormality in ALS and FTD, opened the door to the discovery of several novel pathogenic biological routes, including chromatin remodeling and transcriptome alteration...
October 2016: Acta Neuropathologica
Tanja Grubic Kezele, Gordana Blagojevic Zagorac, Hrvoje Jakovac, Robert Domitrovic, Biserka Radosevic-Stasic
Inflammatory demyelinating diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are often followed by cognitive deficits associated with the neuronal injury, synaptic loss and altered neurogenesis within the hippocampus. Changes depend on the genetic and epigenetic factors that ensure the cellular and environmental homeostasis and regulate the interactions of immunocompetent, glial and neural cells. Owing to high impact of stress proteins on these processes, in this study we compared the protein content of interleukin-6, transforming growth factor-β1, metallothioneins I/II (MTs) and glycoprotein 96 (gp96) in the hippocampus of DA and AO rats that differ in the susceptibility to the induction of EAE, and tested the relationship of MTs and gp96 to granule neurons, glial cells and neural progenitors in different subfields of dentate gyrus...
May 13, 2016: Histology and Histopathology
G Catanzaro, M Pucci, M T Viscomi, M Lanuti, M Feole, S Angeletti, G Grasselli, G Mandolesi, M Bari, D Centonze, C D'Addario, M Maccarrone
The development of multiple sclerosis, a major neurodegenerative disease, is due to both genetic and environmental factors that might trigger aberrant epigenetic changes of the genome. In this study, we analysed global DNA methylation in the brain of mice upon induction of experimental autoimmune encephalomyelitis (EAE), and the effect of environmental enrichment (EE). We demonstrate that global DNA methylation decreased in the striatum, but not in the cortex, of EAE mice compared to healthy controls, in particular in neuronal nitric oxide synthase (nNOS)-positive interneurons of this brain area...
May 15, 2016: Journal of Neuroimmunology
Panagiotis Douvaras, Tomasz Rusielewicz, Kwi Hye Kim, Jeffery D Haines, Patrizia Casaccia, Valentina Fossati
Pluripotent stem cells provide an invaluable tool for generating human, disease-relevant cells. Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system, characterized by myelin damage. Oligodendrocytes are the myelinating cells of the central nervous system (CNS); they differentiate from progenitor cells, and their membranes ensheath axons, providing trophic support and allowing fast conduction velocity. The current understanding of oligodendrocyte biology was founded by rodent studies, where the establishment of repressive epigenetic marks on histone proteins, followed by activation of myelin genes, leads to lineage progression...
2016: International Journal of Molecular Sciences
Marten A Hoeksema, Lisa C Laan, Juliette J Postma, Richard D Cummings, Menno P J de Winther, Christine D Dijkstra, Irma van Die, Gijs Kooij
Helminths have strong immunoregulatory properties that may be exploited in treatment of chronic immune disorders, such as multiple sclerosis and inflammatory bowel disease. Essential players in the pathogenesis of these diseases are proinflammatory macrophages. We present evidence that helminths modulate the function and phenotype of these innate immune cells. We found that soluble products derived from the Trichuris suis (TsSP) significantly affect the differentiation of monocytes into macrophages and their subsequent polarization...
August 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Daniel Golan, Elsebeth Staun-Ram, Ariel Miller
PURPOSE OF REVIEW: In recent years we notice paradigm shifts in the understanding of multiple sclerosis (MS), leading to important transition in the patients' management. This review discusses some of the recent findings and developments underlying the conceptual changes being translated from 'treating the disease' to 'treating the patient' with MS (PwMS). RECENT FINDINGS: Applying advanced technologies combined with cross-disciplinary efforts in the fields of neuropathology, neuroimmunology, neurobiology, and neuroimaging, together with clinical neurology provided support for the notion that MS is not a single disease but rather a spectrum...
June 2016: Current Opinion in Neurology
Haijing Wu, Ming Zhao, Akihiko Yoshimura, Christopher Chang, Qianjin Lu
Autoimmune diseases occur when the immune system loses tolerance to self-antigens, inducing inflammation and tissue damage. The pathogenesis of autoimmune diseases has not been elucidated. A growing mountain of evidence suggests the involvement of genetic and epigenetic factors in the development of these disorders. Genetic mapping has identified several candidate variants in autoimmune conditions. However, autoimmune diseases cannot be explained by genetic susceptibility alone. The fact that there is only 20 % of concordance for systemic lupus erythematosus (SLE) in homozygotic twins is an indication that epigenetics and environment may also play significant roles...
June 2016: Clinical Reviews in Allergy & Immunology
Yamel Rito, Ivan Torre-Villalvazo, José Flores, Verónica Rivas, Teresa Corona
Multiple sclerosis (MS) is a chronic, inflammatory, neurodegenerative demyelinating disease of the central nervous system (CNS). Unfortunately, MS cause important disability in young adults and its prevalence is increasing. While the etiology of MS etiology is not completely understood, it seems to be a multifactorial entity that is influenced by both genetic and epigenetic modifications. Epigenetic mechanisms add or remove different chemical groups for the activation or inhibition of gene expression to block the production of proinflammatory proteins...
February 26, 2016: Central Nervous System Agents in Medicinal Chemistry
Peixing Wan, Wenru Su, Yehong Zhuo
Long noncoding RNAs (lncRNAs) are transcripts with low protein-coding potential but occupy a large part of transcriptional output. Their roles include regulating gene expression at the epigenetic, transcriptional, and post-transcriptional level in cellular homeostasis. However, lncRNA studies are still in their infancy and the functions of the vast majority of lncRNA transcripts remain unknown. It is generally known that the function of the human nervous system largely relies on the precise regulation of gene expression...
February 24, 2016: Molecular Neurobiology
Mireia Guerau-de-Arellano, Yue Liu, Walter H Meisen, David Pitt, Michael K Racke, Amy E Lovett-Racke
Genetic studies suggest that the immune system is the greatest genetic contributor to multiple sclerosis (MS) susceptibility. Yet, these immune-related genes do not explain why inflammation is limited to the CNS in MS. We hypothesize that there is an underlying dysregulation in the CNS of MS patients that makes them more vulnerable to CNS inflammation. The sparsity of CNS-related genes associated with MS suggests that epigenetic changes in the CNS may play a role. Thus, a miRNA profiling study was performed in NAWM of MS patients and control subjects to determine if specific CNS pathways can be identified that may be altered due to miRNA-mediated post-transcriptional dysregulation...
2015: Journal of Autoimmune Disorders
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