Clemastine and metformin extend the window of NMDA receptor surface expression in ageing oligodendrocyte precursor cells.

In the central nervous system, oligodendrocyte precursor cells (OPCs) proliferate and differentiate into myelinating oligodendrocytes throughout life, allowing for ongoing myelination and myelin repair. With age, differentiation efficacy decreases and myelin repair fails; therefore, recent therapeutic efforts have focused on enhancing differentiation. Many cues are thought to regulate OPC differentiation, including neuronal activity, which OPCs can sense and respond to via their voltage-gated ion channels and glutamate receptors. However, OPCs' density of voltage-gated ion channels and glutamate receptors differs with age and brain region, and correlates with their proliferation and differentiation potential, suggesting that OPCs exist in different functional cell states, and that age-associated states might underlie remyelination failure. Here, we use whole-cell patch-clamp to investigate whether clemastine and metformin, two pro-remyelination compounds, alter OPC membrane properties and promote a specific OPC state. We find that clemastine and metformin extend the window of NMDAR surface expression, promoting an NMDAR-rich OPC state. Our findings highlight a possible mechanism for the pro-remyelinating action of clemastine and metformin, and suggest that OPC states can be modulated as a strategy to promote myelin repair.

Periods of synchronized myelin changes shape brain function and plasticity.

Myelin, a lipid membrane that wraps axons, enabling fast neurotransmission and metabolic support to axons, is conventionally thought of as a static structure that is set early in development. However, recent evidence indicates that in the central nervous system (CNS), myelination is a protracted and plastic process, ongoing throughout adulthood. Importantly, myelin is emerging as a potential modulator of neuronal networks, and evidence from human studies has highlighted myelin as a major player in shaping human behavior and learning. Here we review how myelin changes throughout life and with learning. We discuss potential mechanisms of myelination at different life stages, explore whether myelin plasticity provides the regenerative potential of the CNS white matter, and question whether changes in myelin may underlie neurological disorders.

Mitochondrial dynamics and bioenergetics regulated by netrin-1 in oligodendrocytes.

Mitochondria are dynamic organelles that produce energy and molecular precursors that are essential for myelin synthesis. Unlike in neurons, mitochondria in oligodendrocytes increase intracellular movement in response to glutamatergic activation and are more susceptible to oxidative stress than in astrocytes or microglia. The signaling pathways that regulate these cell type-specific mitochondrial responses in oligodendrocytes are not understood. Here, we visualized mitochondria migrating through thin cytoplasmic channels crossing myelin basic protein-positive compacted membranes and localized within paranodal loop cytoplasm. We hypothesized that local extracellular enrichment of netrin-1 might regulate the recruitment and function of paranodal proteins and organelles, including mitochondria. We identified rapid recruitment of mitochondria and paranodal proteins, including neurofascin 155 (NF155) and the netrin receptor deleted in colorectal carcinoma (DCC), to sites of contact between oligodendrocytes and netrin-1-coated microbeads in vitro. We provide evidence that Src-family kinase activation and Rho-associated protein kinase (ROCK) inhibition downstream of netrin-1 induces mitochondrial elongation, hyperpolarization of the mitochondrial inner membrane, and increases glycolysis. Our findings identify a signaling mechanism in oligodendrocytes that is sufficient to locally recruit paranodal proteins and regulate the subcellular localization, morphology, and function of mitochondria.

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 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.

Activity-dependent central nervous system myelination throughout life.

Myelin, the multilayered membrane surrounding many axons in the nervous system, increases the speed by which electrical signals travel along axons and facilitates neuronal communication between distant regions of the nervous system. However, how neuronal signals influence the myelinating process in the CNS is still largely unclear. Recent studies have significantly advanced this understanding, identifying important roles for neuronal activity in controlling oligodendrocyte development and their capacity of producing myelin in both developing and mature CNS. Here, we review these recent advances, and discuss potential mechanisms underpinning activity-dependent myelination and how remyelination may be stimulated via manipulating axonal activity, raising new questions for future research.

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.

Lipidome and proteome map of myelin membranes.

To understand the molecular anatomy of myelin membranes, we performed a large-scale, liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS)-based lipidome and proteome screen on freshly purified human and murine myelin fractions. We identified more than 700 lipid moieties and above 1,000 proteins in the two species, including 284 common lipids and 257 common proteins. This study establishes the first comprehensive map of myelin membrane components in human and mice. Although this study demonstrates many similarities between human and murine myelin, several components have been identified exclusively in each species. Future quantitative validation studies focused on interspecies differences will authenticate the myelin membrane anatomy. The combined lipidome and proteome map presented here can nevertheless be used as a reference library for myelin health and disease.

Implication of perturbed axoglial apparatus in early pediatric multiple sclerosis.

Cerebrospinal fluid samples collected from children during initial presentation of central nervous system inflammation, who may or may not subsequently be diagnosed as having multiple sclerosis (MS), were subjected to large-scale proteomics screening. Unexpectedly, major compact myelin membrane proteins typically implicated in MS were not detected. However, multiple molecules that localize to the node of Ranvier and the surrounding axoglial apparatus membrane were implicated, indicating perturbed axon-glial interactions in those children destined for diagnosis of MS.

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.

MicroRNA dysregulation in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS) demyelination and axonal degeneration. Although the cause of MS is still unknown, it is widely accepted that novel drug targets need to focus on both decreasing inflammation and promoting CNS repair. In MS and experimental autoimmune encephalomyelitis, non-coding small microRNAs (miRNAs) are dysregulated in the immune system and CNS. Since individual miRNAs are able to down-regulate multiple targeted mRNA transcripts, even minor changes in miRNA expression may lead to significant alterations in gene expression. Herein, we review miRNA signatures reported in CNS tissue and immune cells of MS patients and consider how altered miRNA expression may influence MS pathology.

A case report of pernicious anemia and recurrent aphthous stomatitis.

AIM: The aim of this report is to present the management of a patient with pernicious anemia afflicted with recurrent aphthous stomatitis (RAS). BACKGROUND: RAS is one of the most common lesions of the oral mucosa. Although the exact etiology of RAS is still unknown different hematinic deficiencies have been proposed. CASE REPORT: Painful recurrent ulcers covered with a grayish pseudomembrane surrounded by an erythematous margin were identified on the tongue and in the buccal mucosa of a 71-year-old woman. The patient also presented with depapilation of the tongue. The clinical diagnosis was RAS. Laboratory tests including a hemogram were ordered to determine existing levels of folic acid, iron, ferritin, and vitamins B2, B6, and B12. Levels of serum vitamin B12 and serum hemoglobin were low. The laboratory investigation also showed a medium corpuscular volume of 104.1 fl. A gastroduodenoscopy revealed no macroscopic abnormality. A gastric biopsy showed mucosal atrophy in the gastric corpus with evidence of intestinal metaplasia. Antibodies against an intrinsic factor were negative. The diagnosis pernicious anemia was made, with RAS caused by vitamin B12 malabsorption. Treatment consisted of the administration of 1.0 ml of hydroxocolabamin intramuscularly twice weekly over four weeks followed by 1.0 ml once weekly for four weeks. Clinical resolution was observed after two months. SUMMARY: The association of RAS with vitamin B12 malabsorption is a rare event. However, along with conventional RAS clinical management, iron, folic acid, vitamin B deficiencies, and nutritional intolerance must be considered. Evaluation of the predisposing factors is imperative in treating patients with RAS including vitamin B12 malabsorption. CLINICAL SIGNIFICANCE: Determination of the levels of vitamin B12 should be the basis for replacement therapy. Such therapy can be considered a benefit to the patients with RAS as its etiology remains unclear. Clinicians must be alert to the possibility this lesion could be a signal of systemic disease.