Hidden herpes virus may play key role in MS, other brain disorders -- ScienceDaily

 "The ubiquitous human herpesvirus 6 (HHV-6) may play a critical role in impeding the brain's ability to repair itself in diseases like multiple sclerosis. The findings, which appear in the journal Scientific Reports, may help explain the differences in severity in symptoms that many people with the disease experience.

"While latent HHV-6 -- which can be found in cells throughout the brain -- has been associated with demyelinating disorders like multiple sclerosis it has not been clear what role, if any, it plays in these diseases," said Margot Mayer-Proschel, Ph.D., an associate professor at the University of Rochester Medical Center Department of Biomedical Genetics and co-author of the study. "These findings show that, while in the process of hiding from the immune system, the virus produces a protein that has the potential to impair the normal ability of cells in the brain to repair damaged myelin.""



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Signalling through AMPA receptors on oligodendrocyte precursors promotes myelination by enhancing oligodendrocyte survival | eLife

 Myelin, made by oligodendrocytes, is essential for rapid information transfer in the central nervous system. Oligodendrocyte precursors (OPs) receive glutamatergic synaptic input from axons but how this affects their development is unclear. Murine OPs in white matter express AMPA receptor (AMPAR) subunits GluA2, GluA3 and GluA4. We generated mice in which OPs lack both GluA2 and GluA3, or all three subunits GluA2/3/4, which respectively reduced or abolished AMPAR-mediated input to OPs. In both double- and triple-knockouts OP proliferation and number were unchanged but ~25% fewer oligodendrocytes survived in the subcortical white matter during development. In triple knockouts, this shortfall persisted into adulthood. The oligodendrocyte deficit resulted in ~20% fewer myelin sheaths but the average length, number and thickness of myelin internodes made by individual oligodendrocytes appeared normal. Thus, AMPAR-mediated signalling from active axons stimulates myelin production in developing white matter by enhancing oligodendrocyte survival, without influencing myelin synthesis per se.

Epsilon toxin from Clostridium perfringens acts on oligodendrocytes without forming pores, and causes demyelination.

Epsilon toxin (ET) is produced by Clostridium perfringens types B and D and causes severe neurological disorders in animals. ET has been observed binding to white matter, suggesting that it may target oligodendrocytes. In primary cultures containing oligodendrocytes and astrocytes, we found that ET (10(-9) M and 10(-7) M) binds to oligodendrocytes, but not to astrocytes. ET induces an increase in extracellular glutamate, and produces oscillations of intracellular Ca(2+) concentration in oligodendrocytes. These effects occurred without any change in the transmembrane resistance of oligodendrocytes, underlining that ET acts through a pore-independent mechanism. Pharmacological investigations revealed that the Ca(2+) oscillations are caused by the ET-induced rise in extracellular glutamate concentration. Indeed, the blockade of metabotropic glutamate receptors type 1 (mGluR1) prevented ET-induced Ca(2+) signals. Activation of the N-methyl-D-aspartate receptor (NMDA-R) is also involved, but to a lesser extent. Oligodendrocytes are responsible for myelinating neuronal axons. Using organotypic cultures of cerebellar slices, we found that ET induced the demyelination of Purkinje cell axons within 24 h. As this effect was suppressed by antagonizing mGluR1 and NMDA-R, demyelination is therefore caused by the initial ET-induced rise in extracellular glutamate concentration. This study reveals the novel possibility that ET can act on oligodendrocytes, thereby causing demyelination. Moreover, it suggests that for certain cell types such as oligodendrocytes, ET can act without forming pores, namely through the activation of an undefined receptor-mediated pathway.

Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo : Nature : Nature Publishing Group

 Multiple sclerosis involves an aberrant autoimmune response and
progressive failure of remyelination in the central nervous system.
Prevention of neural degeneration and subsequent disability requires
remyelination through the generation of new oligodendrocytes, but
current treatments exclusively target the immune system. Oligodendrocyte
progenitor cells are stem cells in the central nervous system and the
principal source of myelinating oligodendrocytes¹.
These cells are abundant in demyelinated regions of patients with
multiple sclerosis, yet fail to differentiate, thereby representing a
cellular target for pharmacological intervention².
To discover therapeutic compounds for enhancing myelination from
endogenous oligodendrocyte progenitor cells, we screened a library of
bioactive small molecules on mouse pluripotent epiblast
stem-cell-derived oligodendrocyte progenitor cells^{3, 4, 5}.
Here we show seven drugs function at nanomolar doses selectively to
enhance the generation of mature oligodendrocytes from progenitor cells in vitro.
Two drugs, miconazole and clobetasol, are effective in promoting
precocious myelination in organotypic cerebellar slice cultures, and in vivo
in early postnatal mouse pups. Systemic delivery of each of the two
drugs significantly increases the number of new oligodendrocytes and
enhances remyelination in a lysolecithin-induced mouse model of focal
demyelination. Administering each of the two drugs at the peak of
disease in an experimental autoimmune encephalomyelitis mouse model of
chronic progressive multiple sclerosis results in striking reversal of
disease severity. Immune response assays show that miconazole functions
directly as a remyelinating drug with no effect on the immune system,
whereas clobetasol is a potent immunosuppressant as well as a
remyelinating agent. Mechanistic studies show that miconazole and
clobetasol function in oligodendrocyte progenitor cells through
mitogen-activated protein kinase and glucocorticoid receptor signalling,
respectively. Furthermore, both drugs enhance the generation of human
oligodendrocytes from human oligodendrocyte progenitor cells in vitro.
Collectively, our results provide a rationale for testing miconazole
and clobetasol, or structurally modified derivatives, to enhance
remyelination in patients.

Disturbance of Oligodendrocyte Function Plays a Key Role in the Pathogenesis of Schizophrenia and Major Depressive Disorder

The major psychiatric disorders such as schizophrenia (SZ) and major depressive disorder (MDD) are thought to be multifactorial diseases related to both genetic and environmental factors. However, the genes responsible and the molecular mechanisms underlying the pathogenesis of SZ and MDD remain unclear. We previously reported that abnormalities of disrupted-in-Schizophrenia-1 (DISC1) and DISC1 binding zinc finger (DBZ) might cause major psychiatric disorders such as SZ. Interestingly, both DISC and DBZ have been further detected in oligodendrocytes and implicated in regulating oligodendrocyte differentiation. DISC1 negatively regulates the differentiation of oligodendrocytes, whereas DBZ plays a positive regulatory role in oligodendrocyte differentiation. We have reported that repeated stressful events, one of the major risk factors of MDD, can induce sustained upregulation of plasma corticosterone levels and serum/glucocorticoid regulated kinase 1 (Sgk1) mRNA expression in oligodendrocytes. Repeated stressful events can also activate the SGK1 cascade and cause excess arborization of oligodendrocyte processes, which is thought to be related to depressive-like symptoms. In this review, we discuss the expression of DISC1, DBZ, and SGK1 in oligodendrocytes, their roles in the regulation of oligodendrocyte function, possible interactions of DISC1 and DBZ in relation to SZ, and the activation of the SGK1 signaling cascade in relation to MDD.

PLOS ONE: The Effect of Cellular Differentiation on HSV-1 Infection of Oligodendrocytic Cells

Herpes simplex type 1 (HSV-1) is a neurotropic virus that infects many
types of cells. Previous studies have demonstrated that oligodendrocytic
cells are highly susceptible to HSV-1 infection. Here we analysed HSV-1
infection of a human oligodendrocytic cell line, HOG, and
oligodendrocyte precursor cells (OPCs) cultured under growth or
differentiation conditions. In addition to cell susceptibility, the role
of the major cell receptors for viral entry was assessed. Our results
revealed that OPCs and HOG cells cultured under differentiation
conditions became more susceptible to HSV-1. On the other hand, viral
infection induced morphological changes corresponding to differentiated
cells, suggesting that HSV-1 might be inducing cell differentiation. We
also observed colocalization of HVEM and nectin-1 with viral particles,
suggesting that these two major HSV-1 receptors are functional in HOG
cells. Finally, electron microscopy assays indicated that HSV-1 may be
also entering OLs by macropinocytosis depending on their differentiation
stage. In addition, vesicles containing intracellular enveloped virions
observed in differentiated cells point to an endocytic mechanism of
virus entry. All these data are indicative of diverse entry pathways
dependent on the maturation stage of OLs.

DISC1 (Disrupted-in-Schizophrenia-1) Regulates Differentiation of Oligodendrocytes.

Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a
translocation, t(1;11) (q42.1;q14.3), that segregates with major
psychiatric disorders, including schizophrenia, recurrent major
depression and bipolar affective disorder, in a Scottish family. Here we
report that mammalian DISC1 endogenously expressed in oligodendroglial
lineage cells negatively regulates differentiation of oligodendrocyte
precursor cells into oligodendrocytes. DISC1 expression was detected in
oligodendrocytes of the mouse corpus callosum at P14 and P70. DISC1 mRNA
was expressed in primary cultured rat cortical oligodendrocyte
precursor cells and decreased when oligodendrocyte precursor cells were
induced to differentiate by PDGF deprivation. Immunocytochemical
analysis showed that overexpressed DISC1 was localized in the cell
bodies and processes of oligodendrocyte precursor cells and
oligodendrocytes. We show that expression of the myelin related markers,
CNPase and MBP, as well as the number of cells with a matured
oligodendrocyte morphology, were decreased following full length DISC1
overexpression. Conversely, both expression of CNPase and the number of
oligodendrocytes with a mature morphology were increased following
knockdown of endogenous DISC1 by RNA interference. Overexpression of a
truncated form of DISC1 also resulted in an increase in expression of
myelin related proteins and the number of mature oligodendrocytes,
potentially acting via a dominant negative mechanism. We also identified
involvement of Sox10 and Nkx2.2 in the DISC1 regulatory pathway of
oligodendrocyte differentiation, both well-known transcription factors
involved in the regulation of myelin genes.

Activation of NOD2/RIPK2 pathway induces mitochondrial injury to oligodendrocyte precursor cells in vitro and CNS demyelination in vivo.

We examined the activation of innate immune pathway mediated by
nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in
oligodendrocyte precursor cells (OPCs). We show that activation of NOD2
by ligand peptidoglycan (PGN) leads to the recruitment and
phosphorylation of receptor-interacting serine/threonine kinase 2
(RIPK2). Phosphorylation of RIPK2 is followed by phosphorylation of
neuronal nitric oxide synthase (nNOS), increase in NOS activity and
subsequent accumulation of nitric oxide (NO) mediated N-tyrosinylated
compounds in OPCs. The reversal of NOS activity by the nNOS inhibitor
7-nitroindazole (7-NI), but not by the iNOS inhibitor L-canavanine,
supported the conclusion that the increased NOS activity was due to the
selective activation of nNOS in OPCs. In addition, NO mediated injury to
OPC was reflected in reduction in activity of respiratory enzymes such
as complex I and IV, decrease in mitochondrial membrane potential and
release of cytochrome-C from mitochondria. Furthermore, intracerebral
injection of PGN into corpus callosum (CC) of rats led to the
development of demyelination, which appeared as early as by day 3
post-injection, and involved the trunk of the CC by day 14. Accumulation
of N-tyrosinylated proteins was seen in oligodendrocytes in regions of
the CC which were in close proximity to the injection site. Taken
together, these results suggest that PGN induced formation of NO,
mitochondrial dysfunction and accumulation of N-tyrosinylated proteins
in oligodendrocytes are likely mediators of central nervous system
demyelination.

Specific Glial Functions Contribute to Schizophrenia Susceptibility.

 Schizophrenia is a highly polygenic brain disorder. The main hypothesis for disease etiology in schizophrenia primarily focuses on the role of dysfunctional synaptic transmission. Previous studies have therefore directed their investigations toward the role of neuronal dysfunction. However, recent studies have shown that apart from neurons, glial cells also play a major role in synaptic transmission. Therefore, we investigated the potential causal involvement of the 3 principle glial cell lineages in risk to schizophrenia. We performed a functional gene set analysis to test for the combined effects of genetic variants in glial type-specific genes for association with schizophrenia. We used genome-wide association data from the largest schizophrenia sample to date, including 13 689 cases and 18 226 healthy controls. Our results show that astrocyte and oligodendrocyte gene sets, but not microglia gene sets, are associated with an increased risk for schizophrenia. The astrocyte and oligodendrocyte findings are related to astrocyte signaling at the synapse, myelin membrane integrity, glial development, and epigenetic control. Together, these results show that genetic alterations underlying specific glial cell type functions increase susceptibility to schizophrenia and provide evidence that the neuronal hypothesis of schizophrenia should be extended to include the role of glia.

PLOS Biology: Neurotransmitter-Triggered Transfer of Exosomes Mediates Oligodendrocyte–Neuron Communication

 "Reciprocal interactions between neurons and oligodendrocytes are not only crucial for myelination, but also for long-term survival of axons. Degeneration of axons occurs in several human myelin diseases, however the molecular mechanisms of axon-glia communication maintaining axon integrity are poorly understood. Here, we describe the signal-mediated transfer of exosomes from oligodendrocytes to neurons. These endosome-derived vesicles are secreted by oligodendrocytes and carry specific protein and RNA cargo. We show that activity-dependent release of the neurotransmitter glutamate triggers oligodendroglial exosome secretion mediated by Ca2+ entry through oligodendroglial NMDA and AMPA receptors. In turn, neurons internalize the released exosomes by endocytosis. Injection of oligodendroglia-derived exosomes into the mouse brain results in functional retrieval of exosome cargo in neurons. Supply of cultured neurons with oligodendroglial exosomes improves neuronal viability under conditions of cell stress. These findings indicate that oligodendroglial exosomes participate in a novel mode of bidirectional neuron-glia communication contributing to neuronal integrity."

HERV-W envelope protein inhibits oligodendroglial precursor cell differentiation.

Objective: Differentiation of oligodendroglial precursor cells is crucial for central nervous system remyelination and is influenced by both extrinsic and intrinsic factors. Recent studies showed that a human endogenous retrovirus type W (HERV-W) contributes significantly to brain damage. In particular, its envelope protein ENV can mediate injury to specific cell types of the brain and immune system. Here, we investigated whether ENV protein affects oligodendroglial differentiation. Methods: Immunostaining and gene expression analyses were performed to establish the expression and regulation of the known ENV receptor, Toll-like receptor 4 (TLR4), on oligodendroglial precursor cells in human brain tissue and in culture. Cultured primary oligodendroglial precursor cells were stimulated with ENV protein to determine the effects of this ligand/receptor interaction. Results: We demonstrated that the ENV protein is present in close proximity to TLR4-expressing oligodendroglial precursor cells adjacent to multiple sclerosis lesions. Human and rat oligodendroglial precursor cells expressed TLR4, and the ENV-mediated activation of TLR4 led to the induction of proinflammatory cytokines and inducible nitric oxide synthase as well as the formation of nitrotyrosine groups and a subsequent reduction in myelin protein expression. Interpretation: Our findings suggest that ENV-mediated induction of nitrosative stress via activation of TLR4 results in an overall reduction of the oligodendroglial differentiation capacity, thereby contributing to remyelination failure. Therefore, pharmacological or antibody-mediated inhibition of ENV may prevent the blockade of myelin repair in the diseased or injured central nervous system. ANN NEUROL 2013. © 2013 American Neurological Association.

Human but Not Laboratory Borna Disease Virus Inhibits Proliferation and Induces Apoptosis in Human Oligodendrocytes In Vitro.

Borna disease virus (BDV) is a neurotropic virus that produces neuropsychiatric dysfunction in a wide range of warm-blooded species. Several studies have associated BDV with human psychiatric illness, but the findings remain controversial. Although oligodendrocytes are a major glial component of brain white matter and play a pivotal role in neuronal cell function, BDV's effects on human oligodendrocytes have not been clarified. Here, the effects of two BDV strains, Hu-H1 (isolated from a bipolar patient) and Strain V (a laboratory strain), on the proliferation and apoptosis of human oligodendrocytes were investigated. Three experimental cell lines were constructed: Hu-H1-infected oligodendroglioma (Hu-H1) cells, Strain V-infected oligodendroglioma (Strain V) cells, and non-infected oligodendroglioma (control) cells. BDV infection was assayed by BDV nucleoprotein (p40) immunofluorescence, cell proliferation was assayed by Cell Counting Kit-8 (CCK8), and cell cycle phases and apoptosis were assayed by flow cytometry. Expressions of the apoptosis-related proteins Bax and Bcl-2 were measured by Western blotting. p40 expression was confirmed in Hu-H1 and Strain V on and after day three post-infection. Strain V cells showed significantly greater cellular proliferation than Hu-H1 cells on and after day three post-infection. In Hu-H1 cells, Bax and Bcl-2 expression were significantly increased and decreased, respectively, on and after day three post-infection. In contrast, in Strain V cells, Bax and Bcl-2 expression were significantly decreased and increased, respectively, on and after day three post-infection. In conclusion, Hu-H1 inhibits cellular proliferation and promotes apoptosis in human oligodendrocytes via Bax upregulation and Bcl-2 downregulation. In contrast, Strain V promotes cellular proliferation and inhibits apoptosis in human oligodendrocytes via Bax downregulation and Bcl-2 upregulation. The effects of the Hu-H1 strain (isolated from a bipolar patient) are opposite from those of Strain V (a laboratory strain), thereby providing a proof of authenticity for both.

A functional role of NMDA receptor in regulating the differentiation of oligodendrocyte precursor cells and remyelination.

Differentiation of oligodendrocyte precursor cells (OPCs) is the most important event for the myelination of central nervous system (CNS) axons during development and remyelination in demyelinating diseases, while the underlying molecular mechanisms remain largely unknown. Here we show that NMDA receptor (NMDAR) is a functional regulator of OPCs differentiation and remyelination. First, GluN1, GluN2A, and GluN2B subunits are expressed in oligodendrocyte lineage cells (OLs) in vitro and in vivo by immunostaining and Western blot analysis. Second, in a purified rat OPC culture system, NMDARs specially mediate OPCs differentiation by enhancing myelin proteins expression and the processes branching at the immature to mature oligodendrocyte transition analyzed by a serial of developmental stage-specific antigens. Moreover, pharmacological NMDAR antagonists or specific knockdown of GluN1 by RNA interference in OPCs prevents the differentiation induced by NMDA. NMDA can activate the mammalian target of rapamycin (mTOR) signal in OPCs and the pro-differentiation effect of NMDA is obstructed by the mTOR inhibitor rapamycin, suggesting NMDAR exerts its effect through mTOR-dependent mechanism. Furthermore, NMDA increases numbers of myelin segments in DRG-OPC cocultures. Finally, NMDAR specific antagonist MK801 delays remyelination in the cuprizone model examined by LFB-PAS, immunofluorescence and electron microscopy. This effect appears to result from inhibiting OPCs differentiation as more NG2(+) OPCs but less GST-π(+) mature oligodendrocytes are observed. Together, these results indicate that NMDAR plays a critical role in the regulation of OPCs differentiation in vitro and remyelination in cuprizone model which may provide potential target for the treatment of demyelination disease.

Androgenic hormones could help treat multiple sclerosis, study finds

 "Testosterone and its derivatives could constitute an efficient treatment against myelin diseases such as multiple sclerosis, reveals a study by researchers from the Laboratoire d'Imagerie et de Neurosciences Cognitives. Myelin composes the sheaths that protect the nerve fibers and allow the speed of nerve impulses to be increased. A deficit in the production of myelin or its destruction cause serious illnesses for which there is no curative treatment. The researchers have shown that in mice brains whose nerve fibers have been demyelinated, testosterone and a synthetic analog induce the regeneration of oligodendrocytes, the cells responsible for myelination, and that they stimulate remyelination. This work is published on January in the journal Brain."

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The Antiaging Protein Klotho Enhances Oligodendrocyte Maturation and Myelination of the CNS

We have previously shown that myelin abnormalities characterize the normal aging process of the brain and that an age-associated reduction in Klotho is conserved across species. Predominantly generated in brain and kidney, Klotho overexpression extends life span, whereas loss of Klotho accelerates the development of aging-like phenotypes. Although the function of Klotho in brain is unknown, loss of Klotho expression leads to cognitive deficits. We found significant effects of Klotho on oligodendrocyte functions, including induced maturation of rat primary oligodendrocytic progenitor cells (OPCs) in vitro and myelination. Phosphoprotein analysis indicated that Klotho's downstream effects involve Akt and ERK signal pathways. Klotho increased OPC maturation, and inhibition of Akt or ERK function blocked this effect on OPCs. In vivo studies of Klotho knock-out mice and control littermates revealed that knock-out mice have a significant reduction in major myelin protein and gene expression. By immunohistochemistry, the number of total and mature oligodendrocytes was significantly lower in Klotho knock-out mice. Strikingly, at the ultrastructural level, Klotho knock-out mice exhibited significantly impaired myelination of the optic nerve and corpus callosum. These mice also displayed severe abnormalities at the nodes of Ranvier. To decipher the mechanisms by which Klotho affects oligodendrocytes, we used luciferase pathway reporters to identify the transcription factors involved. Together, these studies provide novel evidence for Klotho as a key player in myelin biology, which may thus be a useful therapeutic target in efforts to protect brain myelin against age-dependent changes and promote repair in multiple sclerosis.

How Does Multiple Sclerosis Progress? Possible Clues Discovered: MNT

B cells isolated from multiple sclerosis patients secrete a toxic substance that damages oligodendrocytes

Gemfibrozil, a lipid-lowering drug, increases myelin genes in human oligodendrocytes via peroxisome proliferator-activated receptor beta.

An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis (MS). Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identifies another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (MBP, MOG, CNPase, and PLP) in primary human oligodendrocytes, mixed glial cells and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-a (PPAR-a), we were unable to detect PPAR-a in either gemfibrozil-treated or untreated human oligodendrocytes and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-a (-/-) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-b, but not PPAR-g. Consistently, antisense knockdown of PPAR-b, but not PPAR-g, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not upregulate myelin genes in oligodendroglia isolated from PPAR-b (-/-) mice. Chromatin immunoprecipitation analysis shows that gemfibrozil induces the recruitment of PPAR-b to the promoter of PLP and MOG genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-b to the PLP promoter in vivo in the spinal cord of EAE mice and suppression of EAE symptoms in PLP-TCR transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-b and that gemfibrozil, a prescribed drug for humans, may further find its therapeutic use in demyelinating diseases.

Oligodendroglia cells protect neurons against neurodegeneration

(Medical Xpress) -- Johns Hopkins researchers say they have discovered that the central nervous system's oligodendroglia cells, long believed to simply insulate nerves as they "fire" signals, are unexpectedly also vital to the survival of neurons. Damage to these insulators appears to contribute to brain injury in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease for the Yankee baseball great who died from the disease.

Regulated release of BDNF by cortical oligodendrocytes is mediated through metabotropic glutamate receptors and the PLC pathway.

Regulated release of BDNF by cortical oligodendrocytes is mediated through metabotropic glutamate receptors and the Phospholipase C pathway.

A novel, rapid, quantitative cell-counting method reveals oligodendroglial reduction in the frontopolar cortex in major depressive disorder : Molecular Psychiatry

Oligodendrocyte cell  loss and demyelination are a feature of several psychiatric disorders which should really be considered as degenerative disorders with a clear glial cell basis.

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