Neuroglial interactions underpinning myelin plasticity.

The CNS is extremely responsive to an ever-changing environment. Studies of neural circuit plasticity focus almost exclusively on functional and structural changes of neuronal synapses. In recent years, however, myelin plasticity has emerged as a potential modulator of neuronal networks. Myelination of previously unmyelinated axons and changes in the structure of myelin on already-myelinated axons (similar to changes in internode number and length or myelin thickness or geometry of the nodal area) can in theory have significant effects on the function of neuronal networks. In this article, the authors review the current evidence for myelin changes occurring in the adult CNS, highlight some potential underlying mechanisms of how neuronal activity may regulate myelin changes, and explore the similarities between neuronal and myelin plasticity. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 93-107, 2018.We would like to thank our funders: Lister Institute of Preventive Medicine: Ragnhildur Thóra Káradóttir; Allen Distinguished Investigator programme, through The Paul G. Allen Frontiers Group: Ragnhildur Thóra Káradóttir and Kimberley Evans; Biotechnology and Biological Sciences Research Council (BBSRC) and The Cambridge Trust: E. A. Claudia Pama; UK Multiple Sclerosis Society: Ragnhildur Thóra Káradóttir and Omar de-Faria-jr, Award number 50. The funders had no role in decision to publish, or preparation of the manuscript

Regulation of miRNA 219 and miRNA Clusters 338 and 17-92 in Oligodendrocytes

MicroRNAs (miRs) regulate diverse molecular and cellular processes including oligodendrocyte (OL) precursor cell (OPC) proliferation and differentiation in rodents. However, the role of miRs in human OPCs is poorly understood. To identify miRs that may regulate these processes in humans, we isolated OL lineage cells from human white matter and analyzed their miR profile. Using endpoint RT-PCR assays and quantitative real-time PCR, we demonstrate that miR-219, miR-338, and miR-17-92 are enriched in human white matter and expressed in acutely isolated human OLs. In addition, we report the expression of closely related miRs (miR-219-1-3p, miR-219-2-3p, miR-1250, miR-657, miR-3065-5p, miR-3065-3p) in both rodent and human OLs. Our findings demonstrate that miRs implicated in rodent OPC proliferation and differentiation are regulated in human OLs and may regulate myelination program in humans. Thus, these miRs should be recognized as potential therapeutic targets in demyelinating disorders

TMEM10 Promotes Oligodendrocyte Differentiation and is Expressed by Oligodendrocytes in Human Remyelinating Multiple Sclerosis Plaques.

Oligodendrocyte precursor cells (OPCs) differentiate during postnatal development into myelin-forming oligodendrocytes, in a process distinguished by substantial changes in morphology and the onset of myelin gene expression. A mammalian-specific CNS myelin gene, tmem10, also called Opalin, encodes a type 1 transmembrane protein that is highly upregulated during early stages of OPC differentiation; however, a function for TMEM10 has not yet been identified. Here, consistent with previous studies, we detect TMEM10 protein in mouse brain beginning at ~P10 and show that protein levels continue to increase as oligodendrocytes differentiate and myelinate axons in vivo. We show that constitutive TMEM10 overexpression in the Oli-neu oligodendroglial cell line promotes the expression of the myelin-associated genes MAG, CNP and CGT, whereas TMEM10 knock down in primary OPCs reduces CNP mRNA expression and decreases the percentage of MBP-positive oligodendrocytes that differentiate in vitro. Ectopic TMEM10 expression evokes an increase in process extension and branching, and blocking endogenous TMEM10 expression results in oligodendrocytes with abnormal cell morphology. These findings may have implications for human demyelinating disorders, as oligodendrocytes expressing TMEM10 are detected in human remyelinating multiple sclerosis lesions. Together, our findings provide evidence that TMEM10 promotes oligodendrocyte terminal differentiation and may represent a novel target to promote remyelination in demyelinating disorders

Oligodendrocyte progenitor cells become regionally diverse and heterogeneous with age

Oligodendrocyte progenitor cells (OPCs), which differentiate into myelinating oligodendrocytes during central nervous system (CNS) development, are the main proliferative cells in the adult brain. OPCs are conventionally considered a homogeneous population, particularly with respect to their electrophysiological properties, but this has been debated. We show, by using single-cell electrophysiological recordings, that OPCs start out as a homogeneous population, but become functionally heterogeneous, varying both within and between brain regions and with age. These electrophysiological changes in OPCs correlate with the differentiation potential of OPCs; thus, they may underlie the differentiational differences in OPCs between regions and likewise differentiation failure with age.We acknowledge the support of the Wellcome - MRC Cambridge Stem Cell Institute core facility managers, in particular for this work Dr Maike Paramor and Miss Victoria Murray with RNA sequencing, and all staff members of the University Biomedical Services (UBS). This project has received funding from: the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 771411; R.T.K, K.A.E); the Wellcome Trust, a Research Career Development Fellowship (R.T.K. and K.A.E. 091543/Z/10/Z) and a Studentship (102160/Z/13/Z; Y.K); The Paul G Allen Frontiers Group, Allen Distinguished Investigator Award (12076, R.T.K., D.K.V.); The Medical Research Council, a studentship (S.O.S.); The Gates Foundation, a Gates Scholarship (S.S.), The Biotechnology and Biological Sciences Research Council, a studentship (S.A.); Homerton College Cambridge, a Junior Research Fellowship (D.K.V); The UK MS Society, a Cambridge Myelin Repair Centre grant (50; R.T.K, O.D.F.); The Fonds de recherche du Québec-Santé, a scholarship (Y.K.); The Cambridge Commonwealth European & International Trust, a scholarship (Y.K.); and the Lister Institute, a Research Prize (R.T.K., K.A.E, SOS)

Oligodendrocyte Progenitor Cells Become Regionally Diverse and Heterogeneous with Age

We thank J. Trotter (Johannes Gutenberg University, Mainz, Germany) for the NG2-EYFP mice, Dr. Moritz Matthey for help with minipump transplantation, Miss Mariann Kovacs with embryonic dissection, and Dr. Katrin Volbracht for critical comments on the work. We acknowledge the support of the Wellcome – MRC Cambridge Stem Cell Institute core facility managers, in particular for this work Dr. Maike Paramor and Miss Victoria Murray with RNA-seq, and all staff members of the University Biomedical Services (UBS). This project has received the following funding: funding from the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (grant agreement 771411 to R.T.K. and K.A.E.), a Wellcome Trust research career development fellowship (091543/Z/10/Z to R.T.K. and K.A.E.) and studentship (102160/Z/13/Z to Y.K.), Paul G. Allen Frontiers Group Allen Distinguished Investigator Award 12076 (to R.T.K., D.K.-V., and K.A.E.), a Medical Research Council studentship (to S.O.S.), a Gates Cambridge Trust Gates scholarship (to S.S.), a Biotechnology and Biological Sciences Research Council studentship (to S.A.), a Homerton College Cambridge junior research fellowship (to D.K.-V.), UK MS Society Cambridge Myelin Repair Centre grant 50 (to R.T.K. and O.d.F.), a Fonds de Recherche du Québec - Santé scholarship (to Y.K.), a Cambridge Commonwealth, European and International Trust scholarship (to Y.K.), and a Lister Institute research prize (to R.T.K., K.A.E., and S.O.S.). Publisher Copyright: © 2018 The Author(s)Spitzer et al. show that oligodendrocyte progenitor cells (OPCs) acquire ion channels and sensitivity to neuronal activity that differ between region and age. The onset and decline of ion channels follow developmental milestones. This heterogeneity indicates different functional states of OPCs.Peer reviewe

Impact of safety-related dose reductions or discontinuations on sustained virologic response in HCV-infected patients: Results from the GUARD-C Cohort

BACKGROUND: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. METHODS: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA <50 IU/mL) were conducted in 951 Caucasian, noncirrhotic genotype (G)1 patients assigned to peginterferon alfa-2a/ribavirin for 48 weeks. The probability of SVR24 was identified by a baseline scoring system (range: 0-9 points) on which scores of 5 to 9 and <5 represent high and low probability of SVR24, respectively. RESULTS: SVR24 rates were 46.1% (754/1634), 77.1% (279/362), 68.0% (514/756), and 51.3% (203/396), respectively, in G1, 2, 3, and 4 patients. Overall, 16.9% and 21.8% patients experienced 651 sr-RD for peginterferon alfa and ribavirin, respectively. Among Caucasian noncirrhotic G1 patients: female sex, lower body mass index, pre-existing cardiovascular/pulmonary disease, and low hematological indices were prognostic factors of sr-RD; SVR24 was lower in patients with 651 vs. no sr-RD by Week 4 (37.9% vs. 54.4%; P = 0.0046) and Week 12 (41.7% vs. 55.3%; P = 0.0016); sr-RD by Week 4/12 significantly reduced SVR24 in patients with scores <5 but not 655. CONCLUSIONS: In conclusion, sr-RD to peginterferon alfa-2a/ribavirin significantly impacts on SVR24 rates in treatment-naive G1 noncirrhotic Caucasian patients. Baseline characteristics can help select patients with a high probability of SVR24 and a low probability of sr-RD with peginterferon alfa-2a/ribavirin