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International Journal of Molecular... Apr 2018Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome... (Review)
Review
Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4⁺ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4⁺ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4⁺ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.
Topics: Animals; Circadian Rhythm; Demyelinating Diseases; Energy Metabolism; Humans; Multiple Sclerosis; PPAR gamma; Wnt Signaling Pathway
PubMed: 29659554
DOI: 10.3390/ijms19041212 -
Brain Pathology (Zurich, Switzerland) Jul 1996Demyelination is a pathological feature that is characteristic of many diseases of the central nervous system (CNS) including multiple sclerosis (MS), sub-acute... (Review)
Review
Demyelination is a pathological feature that is characteristic of many diseases of the central nervous system (CNS) including multiple sclerosis (MS), sub-acute sclerosing panencephalomyelitis (SSPE), metachromatic leukodystrophy and Pelizaeus-Merzbacher disease. While demyelination is a pathological end-point that is common to all of these diseases, the cellular and molecular mechanisms responsible for this pathology are very different . These range from genetic defects that affect lipid metabolism in the leukodystrophies, cytopathic effects of viral infection in SSPE to the action of immunological effector mechanisms in MS and the viral encephalopathies. Irrespective of the initial cause of myelin degradation, many of these disorders are associated with some degree of CNS inflammation, as indicated by the local activation of microglia, recruitment of macrophages or the intrathecal synthesis of immunoglobulin. Many of these phenomena are now being duplicated in animal models, providing not only new insights into the pathogenesis of human demyelinating diseases , but also unexpected interrelationships between the immune response in the CNS and the pathogenesis of diseases such as Alzheimers disease and HIV encephalopathy. Autoimmune mediated models of inflammatory demyelinating CNS disease have proved particularly valuable in this respect as they allow the effects of defined immune effector mechanisms to be studied in the absence of CNS infection.
Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Humans
PubMed: 8864286
DOI: 10.1111/j.1750-3639.1996.tb00857.x -
Brain : a Journal of Neurology Mar 2016Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed...
Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies.
Topics: Brain; Brain Mapping; Cerebral Cortex; Cohort Studies; Demyelinating Diseases; Humans; Multiple Sclerosis; Nerve Degeneration; White Matter
PubMed: 26912645
DOI: 10.1093/brain/awv398 -
Journal of Neuroscience Research Dec 2016Oligodendrocytes and their myelin sheaths play an intricate role in axonal health and function. The prevalence of white matter pathology in a wide variety of central... (Review)
Review
Oligodendrocytes and their myelin sheaths play an intricate role in axonal health and function. The prevalence of white matter pathology in a wide variety of central nervous system disorders has gained attention in recent years. Remyelination has therefore become a major target of therapeutic research, with the aim of protecting axons from further damage. The axon-myelin unit is elaborate, and demyelination causes profound changes in axonal molecular domains, signal transmission, and metabolism. Remyelination is known to restore some of these changes, but many of its outcomes remain unknown. Understanding how different aspects of the axon-myelin unit are restored by remyelination is important for making effective, targeted therapeutics for white matter dysfunction. Additionally, understanding how subtle deficits relate to axonal function during demyelination and remyelination may provide clues into the impact of myelin on neuronal circuits. In this review, we discuss the current knowledge of the neuroprotective effects of remyelination, as well as gaps in our knowledge. Finally, we propose systems with unique myelin profiles that may serve as useful models for investigating remyelination efficacy. © 2016 Wiley Periodicals, Inc.
Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Humans; Mice; Myelin Sheath; Neuroprotection; Oligodendroglia
PubMed: 27618492
DOI: 10.1002/jnr.23923 -
Journal of Neurovirology Apr 2003A number of viruses can initiate central nervous system (CNS) diseases that include demyelination as a major feature of neuropathology. In humans, the most prominent... (Review)
Review
A number of viruses can initiate central nervous system (CNS) diseases that include demyelination as a major feature of neuropathology. In humans, the most prominent demyelinating diseases are progressive multifocal leukoencephalopathy, caused by JC papovirus destruction of oligodendrocytes, and subacute sclerosing panencephalitis, an invariably fatal childhood disease caused by persistent measles virus. The most common neurological disease of young adults in the developed world, multiple sclerosis, is also characterized by lesions of inflammatory demyelination; however, the etiology of this disease remains an enigma. A viral etiology is possible, because most demyelinating diseases of known etiology in both man and animals are viral. Understanding of the pathogenesis of virus-induced demyelination derives for the most part from the study of animal models. Studies with neurotropic strains of mouse hepatitis virus, Theiler's virus, and Semliki Forest virus have been at the forefront of this research. These models demonstrate how viruses enter the brain, spread, persist, and interact with immune responses. Common features are an ability to infect and persist in glial cells, generation of predominantly CD8(+) responses, which control and clear the early phase of virus replication but which fail to eradicate the infection, and lesions of inflammatory demyelination. In most cases demyelination is to a limited extent the result of direct virus destruction of oligodendrocytes, but for the most part is the consequence of immune and inflammatory responses. These models illustrate the roles of age and genetic susceptibility and establish the concept that persistent CNS infection can lead to the generation of CNS autoimmune responses.
Topics: Animals; Demyelinating Diseases; Humans; Multiple Sclerosis; Virus Diseases
PubMed: 12707846
DOI: 10.1080/13550280390194046 -
Prion 2013Over the past decade, immunohistochemical studies have provided compelling evidence that gray matter (GM) pathology in multiple sclerosis (MS) is extensive. Until... (Review)
Review
Over the past decade, immunohistochemical studies have provided compelling evidence that gray matter (GM) pathology in multiple sclerosis (MS) is extensive. Until recently, this GM pathology was difficult to visualize using standard magnetic resonance imaging (MRI) techniques. However, with newly developed MRI sequences, it has become clear that GM damage is present from the earliest stages of the disease and accrues with disease progression. GM pathology is clinically relevant, as GM lesions and/or GM atrophy were shown to be associated with MS motor deficits and cognitive impairment. Recent autopsy studies demonstrated significant GM demyelination and microglia activation. However, extensive immune cell influx, complement activation and blood-brain barrier leakage, like in WM pathology, are far less prominent in the GM. Hence, so far, the cause of GM damage in MS remains unknown, although several plausible underlying pathogenic mechanisms have been proposed. This paper provides an overview of GM damage in MS with a focus on its topology and histopathology.
Topics: Animals; Atrophy; Cerebral Cortex; Demyelinating Diseases; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Multiple Sclerosis
PubMed: 23324595
DOI: 10.4161/pri.23499 -
Molecular Neurobiology Jan 2017Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with the majority of cases involving demyelination of peripheral nerves. The... (Review)
Review
Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with the majority of cases involving demyelination of peripheral nerves. The pathogenic mechanisms of demyelinating CMT remain unclear, and no effective therapy currently exists for this disease. The discovery that mutations in different genes can cause a similar phenotype of demyelinating peripheral neuropathy raises the possibility that there may be convergent mechanisms leading to demyelinating CMT pathogenesis. Increasing evidence indicates that ErbB receptor-mediated signaling plays a major role in the control of Schwann cell-axon communication and myelination in the peripheral nervous system. Recent studies reveal that several demyelinating CMT-linked proteins are novel regulators of endocytic trafficking and/or phosphoinositide metabolism that may affect ErbB receptor signaling. Emerging data have begun to suggest that dysregulation of ErbB receptor trafficking and signaling in Schwann cells may represent a common pathogenic mechanism in multiple subtypes of demyelinating CMT. In this review, we focus on the roles of ErbB receptor trafficking and signaling in regulation of peripheral nerve myelination and discuss the emerging evidence supporting the potential involvement of altered ErbB receptor trafficking and signaling in demyelinating CMT pathogenesis and the possibility of modulating these trafficking and signaling processes for treating demyelinating peripheral neuropathy.
Topics: Animals; Charcot-Marie-Tooth Disease; Demyelinating Diseases; ErbB Receptors; Humans; Protein Transport; Signal Transduction
PubMed: 26732592
DOI: 10.1007/s12035-015-9668-2 -
Frontiers in Immunology 2019Akt is a serine/threonine protein kinase that plays a major role in regulating multiple cellular processes. While the isoforms Akt1 and Akt2 are involved in apoptosis...
Akt is a serine/threonine protein kinase that plays a major role in regulating multiple cellular processes. While the isoforms Akt1 and Akt2 are involved in apoptosis and insulin signaling, respectively, the role for Akt3 remains uncertain. Akt3 is predominantly expressed in the brain, and total deletion of Akt3 in mice results in a reduction in brain size and neurodegeneration following injury. Previously, we found that Akt3 mice have a significantly worse clinical course during myelin-oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model in which autoreactive immune cells enter the CNS, resulting in inflammation, demyelination, and axonal injury. Spinal cords of Akt3 mice are severely demyelinated and have increased inflammation compared to WT, suggesting a neuroprotective role for Akt3 during EAE. To specifically address the role of Akt3 in neuroinflammation and maintaining neuronal integrity, we used several mouse strains with different manipulations to Akt3. During EAE, Akt3 mice (with enhanced Akt3 kinase activity) had lower clinical scores, a lag in disease onset, a delay in the influx of inflammatory cells into the CNS, and less axonal damage compared to WT mice. A significant increased efficiency of differentiation toward FOXP3 expressing iTregs was also observed in Akt3 mice relative to WT. Mice with a conditional deletion of Akt3 in CD4 T-cells had an earlier onset of EAE symptoms, increased inflammation in the spinal cord and brain, and had fewer FOXP3 cells and mRNA expression. No difference in EAE outcome was observed when Akt3 expression was deleted in neurons (Syn1-CKO). These results indicate that Akt3 signaling in T-cells and not neurons is necessary for maintaining CNS integrity during an inflammatory demyelinating disease.
Topics: Animals; Biomarkers; Demyelinating Diseases; Disease Models, Animal; Disease Susceptibility; Encephalomyelitis, Autoimmune, Experimental; Fluorescent Antibody Technique; Forkhead Transcription Factors; Immunohistochemistry; Immunophenotyping; Mice; Mice, Knockout; Proto-Oncogene Proteins c-akt; RNA, Messenger; Signal Transduction; Spinal Cord; T-Lymphocyte Subsets
PubMed: 31404142
DOI: 10.3389/fimmu.2019.01738 -
Journal of Biosciences Dec 2018The gap junctions (GJs), which form intercellular communicating channels between two apposing cells or form hemichannel with extracellular environment, perform crucial... (Review)
Review
The gap junctions (GJs), which form intercellular communicating channels between two apposing cells or form hemichannel with extracellular environment, perform crucial functions to maintain small molecule homeostasis. The central nervous system (CNS) GJs are important for maintenance of myelin sheath and neuronal activity. Connexin (Cx) proteins are building blocks of GJs. Recent cell-biological investigations show that amongst the CNS specific Cxs, the most abundant Cx protein, Cx43 and its oligodendrocytic coupling partner Cx47 primarily important for maintenance of CNS myelin. Recent investigations elucidate that the expression of Cx43 and Cx47 is very important to maintain K? buffering and nutrient homeostasis in oligodendrocytes, CNS myelin and oligodendrocyte function. The investigations on Multiple Sclerosis (MS) patient samples and EAE hypothesized that the functional loss of Cx43/Cx47 could be associated with spread of chronic MS lesions. Exploring the mechanism of initial GJ alteration and its effect on demyelination in this model of MS might play a primary role to understand the basis of altered CNS homeostasis, observed during MS. In this review, we mainly discuss the role of CNS GJs, specifically the Cx43/Cx47 axis in the perspective of demyelination.
Topics: Animals; Astrocytes; Cell Communication; Central Nervous System; Connexin 43; Connexins; Demyelinating Diseases; Disease Models, Animal; Gap Junctions; Gene Expression Regulation; Humans; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Remyelination; Signal Transduction
PubMed: 30541963
DOI: 10.1007/s12038-018-9811-0 -
Stem Cell Reports Jul 2021In response to corpus callosum (CC) demyelination, subventricular zone-derived neural progenitors (SVZdNPs) are mobilized and generate new myelinating oligodendrocytes...
In response to corpus callosum (CC) demyelination, subventricular zone-derived neural progenitors (SVZdNPs) are mobilized and generate new myelinating oligodendrocytes (OLG). Here, we examine the putative immunomodulatory properties of endogenous SVZdNPs during demyelination in the cuprizone model. SVZdNP density was higher in the lateral and rostral CC regions, and demyelination was inversely correlated with activated microglial density and pro-inflammatory cytokine levels. Single-cell RNA sequencing showed that CC areas with high levels of SVZdNP mobilization were enriched in a microglial cell subpopulation with an immunomodulatory signature. We propose MFGE8 (milk fat globule-epidermal growth factor-8) and β3 integrin as a ligand/receptor pair involved in dialogue between SVZdNPs and microglia. Immature SVZdNPs mobilized to the demyelinated CC were found highly enriched in MFGE8, which promoted the phagocytosis of myelin debris in vitro. Overall, these results demonstrate that, in addition to their cell replacement capacity, endogenous progenitors have immunomodulatory properties, highlighting a new role for endogenous SVZdNPs in myelin regeneration.
Topics: Animals; Cell Differentiation; Corpus Callosum; Cuprizone; Demyelinating Diseases; Inflammation; Lateral Ventricles; Ligands; Mice, Transgenic; Microglia; Neural Stem Cells; Neuroprotection; Receptors, Cell Surface
PubMed: 34087164
DOI: 10.1016/j.stemcr.2021.05.002