miRNA dysregulation as the source of the disease

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frodo
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miRNA dysregulation as the source of the disease

Post by frodo » Mon Oct 16, 2017 11:28 pm

Micro-RNA (miRNA) has been proposed as a biomarker of axon degeneration, but some authors have proposed that they could be the source of the disease:

Source: https://www.ncbi.nlm.nih.gov/pubmed/28990564

"The etiology of the disease remains unclear but the recent discovery of a dysregulated miRNA network in both cells and extracellular fluids of MS patients has brought new insights on the pathophysiological mechanisms involved in this disorder. miRNAs can induce a T cell polarization towards a pathological Th17 or Th1 phenotype and a deleterious activation of microglia, the CNS-resident macrophages"

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Petr75
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Re: miRNA dysregulation as the source of the disease

Post by Petr75 » Sat Mar 16, 2019 7:11 am

2019 Feb 8
Pirogov Russian National Research Medical University, Moscow, Russia
MiRNAs from DLK1-DIO3 Imprinted Locus at 14q32 are Associated with Multiple Sclerosis: Gender-Specific Expression and Regulation of Receptor Tyrosine Kinases Signaling.
https://www.ncbi.nlm.nih.gov/pubmed/30743997

Abstract
Relapsing-remitting multiple sclerosis (RRMS) is the most prevalent course of multiple sclerosis. It is an autoimmune inflammatory disease of the central nervous system. To investigate the gender-specific involvement of microRNAs (miRNAs) in RRMS pathogenesis, we compared miRNA profiles in peripheral blood mononuclear cells separately in men and women (eight RRMS patients versus four healthy controls of each gender) using high-throughput sequencing. In contrast to women, six downregulated and 26 upregulated miRNAs (padj < 0.05) were identified in men with RRMS. Genes encoding upregulated miRNAs are co-localized in DLK1-DIO3 imprinted locus on human chromosome 14q32. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis was performed in independent groups of men (16 RRMS patients and 10 healthy controls) and women (20 RRMS patients and 10 healthy controls). Increased expression of miR-431, miR-127-3p, miR-379, miR-376c, miR-381, miR-410 and miR-656 was again demonstrated in male (padj < 0.05), but not in female RRMS patients. At the same time, the expression levels of these miRNAs were lower in healthy men than in healthy women, whereas in RRMS men they increased and reached or exceeded levels in RRMS women. In general, we demonstrated that expression levels of these miRNAs depend both on "health⁻disease" status and gender. Network-based enrichment analysis identified that receptor tyrosine kinases-activated pathways were enriched with products of genes targeted by miRNAs from DLK1-DIO3 locus. These results suggest the male-specific involvement of these miRNAs in RRMS pathogenesis via regulation of PI3K/Akt signaling.

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Re: miRNA dysregulation as the source of the disease

Post by frodo » Wed Mar 20, 2019 8:11 am

Thanks. Quite interesting. It seems that this week we have more news about miRNA disregulation.

Epstein-Barr virus and miRNAs: partners in crime in the pathogenesis of multiple sclerosis?

https://www.frontiersin.org/articles/10 ... 5/abstract

MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression post transcriptionally. In healthy individuals, miRNAs contribute to maintaining gene expression homeostasis. However, the level of miRNAs expressed is markedly altered in different diseases, including multiple sclerosis (MS).

The impact of such changes is being investigated, and thought to shape the immune system into the inflammatory autoimmune phenotype. Much is yet to be learned about the contribution of miRNAs in the molecular pathology of MS. Epstein-Barr virus (EBV) infection is a major risk factor for the development of MS. EBV encodes more than 40 miRNAs, most of which have been studied in the context of EBV associated cancers.

These viral miRNAs regulate genes involved in cell apoptosis, antigen presentation and recognition, as well as B cell transformation. If EBV infection contributes to the pathology of MS, it is plausible that EBV miRNAs may be involved. Unfortunately, there are limited studies addressing how EBV miRNAs are involved in the pathogenesis of MS.

This review summarizes what has been reported regarding cellular and viral miRNA profiles in MS and proposes possible interactions between the two in the development of MS.

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Re: miRNA dysregulation as the source of the disease

Post by Petr75 » Thu Apr 11, 2019 10:16 am

2019 Mar 6
Cellular Neurobiology, Institute for Developmental Biology and Neurobiology, Johannes Gutenberg-University of Mainz, Mainz, Germany
Missing in Action: Dysfunctional RNA Metabolism in Oligodendroglial Cells as a Contributor to Neurodegenerative Diseases?
https://www.ncbi.nlm.nih.gov/pubmed/30843138

Abstract
The formation of myelin around axons by oligodendrocytes (OL) poses an enormous synthetic and energy challenge for the glial cell. Local translation of transcripts, including the mRNA for the essential myelin protein Myelin Basic Protein (MBP) at the site of myelin deposition has been recognised as an efficient mechanism to assure proper myelin sheath assembly. Oligodendroglial precursor cells (OPCs) form synapses with neurons and may localise many additional mRNAs in a similar fashion to synapses between neurons. In some diseases in which demyelination occurs, an abundance of OPCs is present but there is a failure to efficiently remyelinate and to synthesise MBP. This compromises axonal survival and function. OPCs are especially sensitive to cellular stress as occurring in neurodegenerative diseases, which can impinge on their ability to translate mRNAs into protein. Stress causes the build up of cytoplasmic stress granules (SG) in which many RNAs are sequestered and translationally stalled until the stress ceases. Chronic stress in particular could convert this initially protective reaction of the cell into damage, as persistence of SG may lead to pathological aggregate formation or long-term translation block of SG-associated RNAs. The recent recognition that many neurodegenerative diseases often exhibit an early white matter pathology with a proliferation of surviving OPCs, renders a study of the stress-associated processes in oligodendrocytes and OPCs especially relevant. Here, we discuss a potential dysfunction of RNA regulation in myelin diseases such as Multiple Sclerosis (MS) and Vanishing white matter disease (VWM) and potential contributions of OL dysfunction to neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Fragile X syndrome (FXS).

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Re: miRNA dysregulation as the source of the disease

Post by Petr75 » Thu Apr 11, 2019 11:43 am

2019 Feb
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran AND Immunology Research Center, Iran University of Medical Sciences, Tehran, Iran
Altered Expression of miR-326 in T Cell-derived Exosomes of Patients with Relapsing-remitting Multiple Sclerosis.
https://www.ncbi.nlm.nih.gov/pubmed/30848579

Abstract

Invasion of auto-reactive CD4+ T cells especially Th17 into central nervous system (CNS) is an underlying pathogenic mechanism in multiple sclerosis (MS). CD4+ T cells release exosomes which are enriched in microRNAs, reflective of cell's physiological or pathological condition. Thus exosomes could be potent agents to provide quantitative and qualitative information about involved cells in MS. We investigated the expression of pathogenic microRNAs in T cells-derived exosomes of MS patients or healthy controls. Conventional T cells (Tconv) derived from relapsing-remitting (RR) MS patients (n=10) and healthy controls (n=10) were purified and cultured for 3 days by soluble anti-CD3/CD28. Exosomes were purified from cultured-T cells supernatants. The expression levels of exosomal miR-146a, miR-29a, miR-155, and miR-326 were quantified by real-time PCR. A statistically significant increased expression of miR-326 in Tconv-derived exosomes was observed in RRMS patients as compared with controls (7.5±1.88vs 2.51±0.9 p=0.03), On the contrary, no differences were found in the expression levels of miR-155, miR-146a, and miR-29a, in Tconv-derived exosomes of patients as compared with controls (p>0.05). Our results point to altered expression in exosome-derived microRNAs. MiR-326 was previously shown to play a role in the immunopathogenesis of MS by inducing TH17 differentiation and maturation. Therefore, miR-326 containing exosomes might also be a potential clinical target in course of MS. Moreover, the deregulation of this miRNA in exosomes may serve as a diagnostic and prognostic biomarker.

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Re: miRNA dysregulation as the source of the disease

Post by Petr75 » Sat Apr 27, 2019 9:49 pm

2019 Mar 5
Faculty of Biology, Institute for Developmental Biology and Neurobiology, Center of Computational Sciences Mainz (CSM), Johannes Gutenberg University Mainz, Mainz, Germany
Common miRNA Patterns of Alzheimer's Disease and Parkinson's Disease and Their Putative Impact on Commensal Gut Microbiota.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411762/

Abstract
With the rise of Next-Generation-Sequencing (NGS) methods, Micro-RNAs (miRNAs) have achieved an important position in the research landscape and have been found to present valuable diagnostic tools in various diseases such as multiple sclerosis or lung cancer. There is also emerging evidence that miRNAs play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) or Parkinson's disease (PD). Apparently, these diseases come along with changes in miRNA expression patterns which led to attempts from researchers to use these small RNA species from several body fluids for a better diagnosis and in order to observe disease progression. Additionally, it became evident that microbial commensals might play an important role for pathology development and were shown to have a significantly different composition in patients suffering from neurodegeneration compared with healthy controls. As it could recently be shown that secreted miRNAs are able to enter microbial organisms, it is conceivable that the host's miRNA might affect the gut microbial ecosystem. As such, miRNAs may inherit a central role in shaping the "diseased microbiome" and thereby mutually act on the characteristics of these neurodegenerative diseases. We have therefore (1) compiled a list of miRNAs known to be associated with AD and/or PD, (2) performed an in silico target screen for binding sites of these miRNA on human gut metagenome sequences and (3) evaluated the hit list for interesting matches potentially relevant to the etiology of AD and or PD. The examination of protein identifiers connected to bacterial secretion system, lipopolysaccharide biosynthesis and biofilm formation revealed an overlap of 37 bacterial proteins that were targeted by human miRNAs. The identified links of miRNAs to the biological processes of bacteria connected to AD and PD have yet to be validated via in vivo experiments. However, our results show a promising new approach for understanding aspects of these neurodegenerative diseases in light of the regulation of the microbiome.

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Re: miRNA dysregulation as the source of the disease

Post by Petr75 » Sun May 12, 2019 8:46 am

2019 Apr 15
Division of Neuroimmunology, Department of Neurology, University of Rostock, 18147 Rostock, Germany
Dysregulation of Inflammasome Priming and Activation by MicroRNAs in Human Immune-Mediated Diseases
https://www.ncbi.nlm.nih.gov/pubmed/30962309

Abstract
Inflammasomes are protein complexes that respond to a wide range of pathogens and cellular damage signals. Their activation prompts the caspase-1-mediated cleavage of the proinflammatory cytokines IL-1β and IL-18. Inflammasome dysregulation has been demonstrated to play a role in a range of diseases involving the adaptive immune system like multiple sclerosis, rheumatic diseases, and type 1 diabetes. Priming and activation of inflammasomes can be modulated by microRNAs (miRNAs), small noncoding RNAs that regulate gene expression posttranscriptionally. miRNAs, such as miR-223-3p, have been demonstrated to directly target the inflammasome components NLRP3, caspase-1, and caspase-8. Other miRNAs like miR-155-5p modulate TLR-, IL-1R-, TNFR-, and IFNAR-mediated signaling pathways upstream of the inflammasomes. In this study, we discuss how a more detailed elucidation of miRNA-driven inflammasome regulation helps in understanding the molecular processes underlying immune-mediated human diseases, holds potential for the identification of biomarkers and may offer novel targets for the development of future therapeutics.

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Re: miRNA dysregulation as the source of the disease

Post by Petr75 » Sat Jul 13, 2019 11:12 am

2019 May 25
Department of Neurology, Laboratory of Neuroimmunology, Collegium Medicum, University of Warmia and Mazury, Olsztyn, Poland
Circular RNAs as a novel layer of regulatory mechanism in multiple sclerosis.
https://www.ncbi.nlm.nih.gov/pubmed/31163273

Abstract
Multiple sclerosis (MS) is believed to be an autoimmune disease of the central nervous system (CNS) in which autoreactive immune cells recognizing myelin antigens lead to demyelination and axonal injury. Mechanisms inducing and controlling the pathogenesis of MS have not been fully elucidated. Recent studies suggest an important role of epigenetic processes during the development of MS. One of the most significant discoveries in the field of epigenetic contribution to immune response has been the recognition of a group of microRNAs (miRNAs). These single-stranded non-coding RNA molecules regulate the expression of genes encoding proteins and have already been shown to be involved in pathogenesis of MS. Some miRNAs enhance generation of pro-inflammatory immune cells by promoting Th1 and Th17 pathways and others contribute to regulatory and tissue repair processes. The miRNA-dependent controlling process of autoimmune reactions is highly complex because of miRNA redundancy and multitarget nature of most of these molecules. Recently it was discovered that circular RNAs (circRNA) representing a new class of RNA possess a unique ability to control miRNAs by blocking their activity. CircRNAs are called natural miRNA "sponges" as the single circRNA molecule is able to neutralize several miRNAs and thus might determine the availability of miRNAs for their posttranscription regulation. Thus, circRNAs emerged as critical factors in epigenetic regulation of many human diseases including MS. In addition, in contrary to other RNA species they are very stable in the blood and other biological fluids and thus might be considered as a candidate for a biomarker of MS.

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Re: miRNA dysregulation as the source of the disease

Post by Petr75 » Thu Sep 05, 2019 10:03 am

2019 Jun 26
Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, China
Roles of circular RNAs in immune regulation and autoimmune diseases
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594938/

Abstract
Circular RNAs (circRNAs), as a novel class of endogenously expressed non-coding RNAs (ncRNAs), have a high stability and often present tissue-specific expression and evolutionary conservation. Emerging evidence has suggested that circRNAs play an essential role in complex human pathologies. Notably, circRNAs, important gene modulators in the immune system, are strongly associated with the occurrence and development of autoimmune diseases. Here, we focus on the roles of circRNAs in immune cells and immune regulation, highlighting their potential as biomarkers and biological functions in autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), primary biliary cholangitis (PBC), and psoriasis, aiming at providing new insights into the diagnosis and therapy of these diseases.

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Re: miRNA dysregulation as the source of the disease

Post by Petr75 » Sat Sep 07, 2019 7:02 am

2019 Jun 25
Laboratorio di Farmacologia Molecolare e Cellulare della Trasmissione Purinergica, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano, Italy
MicroRNAs change the games in central nervous system pharmacology
https://www.ncbi.nlm.nih.gov/pubmed/31251938

Abstract
MicroRNAs (miRNAs) represent a class of important post-transcriptional regulators of gene expression, enabling cells to follow their intrinsic developmental program. By directly binding to their targets, miRNAs can both promote transcriptional patterns in crucial steps of cell growth, and act as powerful buffering system that titrate protein content in case of aberrant gene expression. The literature of the last decade showed that the presence of tissue-enriched miRNAs in body fluids could be reminiscent of disease state. This is particularly relevant in neurodegenerative disorders, in which peripheral biomarkers could be helpful means to detect disease onset. However, dysregulation of miRNAs is not merely a consequence of disease, but directly contributes to pathological outcomes. On this basis, increasing interest is growing in the development of pharmacological agents targeting specific miRNAs. Actually, this apparently futuristic approach is already part of the current therapies. In fact, several drugs approved for CNS disorders, such as L-Dopa or valproic acid, were also demonstrated to restore some miRNAs. Moreover, ongoing clinical trials demonstrated that miRNA-based drugs are effective against tumors, suggesting that miRNAs also represent a promising class of therapeutic molecules. However, several issues still need to be addressed, particularly in case of CNS diseases, in which stability and delivery are crucial aspects of the therapy. In this commentary, we highlighted potential advantages and limitations of miRNAs as next generation targets in CNS pharmacology, focusing on multiple sclerosis, a chronic demyelinating disease lacking specific therapeutic targets and bona-fide biomarkers.

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