A retroviral link to vertebrate myelination through retrotransposon-RNA-mediated control of myelin gene expression.

Myelin, the insulating sheath that surrounds neuronal axons, is produced by oligodendrocytes in the central nervous system (CNS). This evolutionary innovation, which first appears in jawed vertebrates, enabled rapid transmission of nerve impulses, more complex brains, and greater morphological diversity. Here, we report that RNA-level expression of RNLTR12-int, a retrotransposon of retroviral origin, is essential for myelination.

Mertk-expressing microglia influence oligodendrogenesis and myelin modelling in the CNS.

Background: Microglia, an immune cell found exclusively within the CNS, initially develop from haematopoietic stem cell precursors in the yolk sac and colonise all regions of the CNS early in development. Microglia have been demonstrated to play an important role in the development of oligodendrocytes, the myelin producing cells in the CNS, as well as in myelination. Mertk is a receptor expressed on microglia that mediates immunoregulatory functions, including myelin efferocytosis.

Monitoring recovery after CNS demyelination, a novel tool to de-risk pro-remyelinating strategies.

In multiple sclerosis, while remarkable progress has been accomplished to control the inflammatory component of the disease, repair of demyelinated lesions is still an unmet need. Despite encouraging results generated in experimental models, several candidates favouring or promoting remyelination have not reached the expected outcomes in clinical trials. One possible reason for these failures is that, in most cases, during preclinical testing, efficacy was evaluated on histology only, while functional recovery had not been assessed.

Endogenous clues promoting remyelination in multiple sclerosis.

Purpose Of Review: The introduction some 30 years ago of β-interferon, followed by a panel of immunomodulators and immunosuppressants has led to a remarkable improvement in the management of multiple sclerosis (MS) patients. Despite these noticeable progresses, which lower the number of relapses and thereby ameliorate patients' quality of life, preventing long-term progression of disability is still an unmet need, highlighting the necessity to develop therapeutic strategies aimed at repairing demyelinated lesions and protecting axons from degeneration. The capacity of human brain to self-regenerate demyelinated lesion has opened a field of research aimed at fostering this endogenous potential.

Increased Remyelination and Proregenerative Microglia Under Siponimod Therapy in Mechanistic Models.

Background And Objectives: Siponimod is an oral, selective sphingosine-1-phosphate receptor-1/5 modulator approved for treatment of multiple sclerosis.

Methods: Mouse MRI was used to investigate remyelination in the cuprizone model. We then used a conditional demyelination model to assess the dose-response of siponimod on remyelination.

Teriflunomide Promotes Oligodendroglial 8,9-Unsaturated Sterol Accumulation and CNS Remyelination.

Background And Objectives: To test whether low concentrations of teriflunomide (TF) could promote remyelination, we investigate the effect of TF on oligodendrocyte in culture and on remyelination in vivo in 2 demyelinating models.

Methods: The effect of TF on oligodendrocyte precursor cell (OPC) proliferation and differentiation was assessed in vitro in glial cultures derived from neonatal mice and confirmed on fluorescence-activated cell sorting-sorted adult OPCs. The levels of the 8,9-unsaturated sterols lanosterol and zymosterol were quantified in TF- and sham-treated cultures.

Bruton's Tyrosine Kinase Inhibition Promotes Myelin Repair.

Background: Microglia are the resident macrophages of the central nervous system (CNS). In multiple sclerosis (MS) and related experimental models, microglia have either a pro-inflammatory or a pro-regenerative/pro-remyelinating function. Inhibition of Bruton's tyrosine kinase (BTK), a member of the Tec family of kinases, has been shown to block differentiation of pro-inflammatory macrophages in response to granulocyte-macrophage colony-stimulating factor .

Myelin replacement triggered by single-cell demyelination in mouse cortex.

Myelin, rather than being a static insulator of axons, is emerging as an active participant in circuit plasticity. This requires precise regulation of oligodendrocyte numbers and myelination patterns. Here, by devising a laser ablation approach of single oligodendrocytes, followed by in vivo imaging and correlated ultrastructural reconstructions, we report that in mouse cortex demyelination as subtle as the loss of a single oligodendrocyte can trigger robust cell replacement and remyelination timed by myelin breakdown.

Remyelination in multiple sclerosis: from basic science to clinical translation.

The treatment of multiple sclerosis has been transformed by the successful development of immunotherapies that efficiently reduce disease activity and related clinical relapses during the relapsing-remitting phase of the disease. However, the prevention of disability progression, which is due to axonal and neuronal damage and loss, has yet to be achieved and is therapeutically challenging, particularly during the progressive phase of the disease. One strategy to counteract neurodegeneration is to promote neuroprotection by enhancing myelin regeneration, hence restoring nerve conduction and metabolic support to the axon.

The ENDpoiNTs Project: Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity.

Ubiquitous exposure to endocrine-disrupting chemicals (EDCs) has caused serious concerns about the ability of these chemicals to affect neurodevelopment, among others. Since endocrine disruption (ED)-induced developmental neurotoxicity (DNT) is hardly covered by the chemical testing tools that are currently in regulatory use, the Horizon 2020 research and innovation action ENDpoiNTs has been launched to fill the scientific and methodological gaps related to the assessment of this type of chemical toxicity. The ENDpoiNTs project will generate new knowledge about ED-induced DNT and aims to develop and improve in vitro, in vivo, and in silico models pertaining to ED-linked DNT outcomes for chemical testing.

Problems and Pitfalls of Identifying Remyelination in Multiple Sclerosis.

Regenerative medicines that promote remyelination in multiple sclerosis (MS) are making the transition from laboratory to clinical trials. While animal models provide the experimental flexibility to analyze mechanisms of remyelination, here we discuss the challenges in understanding where and how remyelination occurs in MS.

Evolution of glial wrapping: A new hypothesis.

Animals are able to move and react in numerous ways to external stimuli. Thus, environmental stimuli need to be detected, information must be processed and finally an output decision must be transmitted to the musculature to get the animal moving. All these processes depend on the nervous system which comprises an intricate neuronal network and many glial cells.

Role of a Contactin multi-molecular complex secreted by oligodendrocytes in nodal protein clustering in the CNS.

The fast and reliable propagation of action potentials along myelinated fibers relies on the clustering of voltage-gated sodium channels at nodes of Ranvier. Axo-glial communication is required for assembly of nodal proteins in the central nervous system, yet the underlying mechanisms remain poorly understood. Oligodendrocytes are known to support node of Ranvier assembly through paranodal junction formation.

Conditional Demyelination and Remyelination in a Transgenic Xenopus laevis.

Multiple sclerosis (MS) is the first cause of acquired disability progression in the young adult. Pathology of MS associates inflammation, demyelination, and neurodegeneration. The development of immunotherapies, by reducing the relapse rate, has profoundly impacted short-term prognosis and patients' quality of life.

Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8.

Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk-associated genes.

Transient hypothyroidism favors oligodendrocyte generation providing functional remyelination in the adult mouse brain.

In the adult brain, both neurons and oligodendrocytes can be generated from neural stem cells located within the Sub-Ventricular Zone (SVZ). Physiological signals regulating neuronal glial fate are largely unknown. Here we report that a thyroid hormone (T)-free window, with or without a demyelinating insult, provides a favorable environment for SVZ-derived oligodendrocyte progenitor generation.

The Xenopus tadpole: An in vivo model to screen drugs favoring remyelination.

Background: In multiple sclerosis, development of screening tools for remyelination-promoting molecules is timely.

Objective: A Xenopus transgenic line allowing conditional ablation of myelinating oligodendrocytes has been adapted for in vivo screening of remyelination-favoring molecules.

Methods: In this transgenic, the green fluorescent protein reporter is fused to E.

Recent achievements in stem cell-mediated myelin repair.

Purpose Of Review: Following the establishment of a number of successful immunomodulatory treatments for multiple sclerosis, current research focuses on the repair of existing damage.

Recent Findings: Promotion of regeneration is particularly important for demyelinated areas with degenerated or functionally impaired axons of the central nervous system's white and gray matter. As the protection and generation of new oligodendrocytes is a key to the re-establishment of functional connections, adult oligodendrogenesis and myelin reconstitution processes are of primary interest.

Repair strategies for multiple sclerosis: challenges, achievements and perspectives.

Purpose Of Review: Despite major progress in multiple sclerosis (MS) treatment, to date, accumulation of irreversible clinical disability is not sufficiently prevented with immunotherapies. In this context, repair strategies aimed at reducing axonal damage are becoming a very active field of preclinical and clinical research.

Recent Findings: Improved understanding of the cellular and molecular mechanisms of myelin repair, together with the emergence of new therapeutic candidates are paving the way for novel therapeutic strategies in MS.

Chd7 cooperates with Sox10 and regulates the onset of CNS myelination and remyelination.

Mutations in CHD7, encoding ATP-dependent chromodomain helicase DNA-binding protein 7, in CHARGE syndrome lead to multiple congenital anomalies, including craniofacial malformations, neurological dysfunction and growth delay. Mechanisms underlying the CNS phenotypes remain poorly understood. We found that Chd7 is a direct transcriptional target of oligodendrogenesis-promoting factors Olig2 and Smarca4/Brg1 and is required for proper onset of CNS myelination and remyelination.

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis.

Background: Quantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B ([ C]PiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS.

Methods: Patients with active relapsing-remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with [ C]PiB and magnetic resonance imaging.