Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and ...disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.
Trisomy 21, or Down syndrome (DS), is the most common genetic cause of developmental delay and intellectual disability. To gain insight into the underlying molecular and cellular pathogenesis, we ...conducted a multi-region transcriptome analysis of DS and euploid control brains spanning from mid-fetal development to adulthood. We found genome-wide alterations in the expression of a large number of genes, many of which exhibited temporal and spatial specificity and were associated with distinct biological processes. In particular, we uncovered co-dysregulation of genes associated with oligodendrocyte differentiation and myelination that were validated via cross-species comparison to Ts65Dn trisomy mice. Furthermore, we show that hypomyelination present in Ts65Dn mice is in part due to cell-autonomous effects of trisomy on oligodendrocyte differentiation and results in slower neocortical action potential transmission. Together, these results identify defects in white matter development and function in DS, and they provide a transcriptional framework for further investigating DS neuropathogenesis.
•Genome-wide spatiotemporal dysregulation of gene expression is found in DS brains•Transcriptome changes reflect altered oligodendrocyte development and myelination•Oligodendrocyte differentiation and myelination is altered in DS model mice (Ts65Dn)•Speed of action potential propagation is decreased in Ts65Dn neocortical white matter
Olmos-Serrano et al. identify defects in oligodendrocyte differentiation and white matter development over the timespan in Down syndrome (DS) brain and in Ts65Dn trisomic mice. Their developmental gene expression study provides a new framework for investigating DS neuropathogenesis.
In the vertebrate nervous system, myelination of axons for rapid impulse propagation requires the synthesis of large amounts of lipids and proteins by oligodendrocytes and Schwann cells. Myelin ...membranes are thought to be cell-autonomously assembled by these axon-associated glial cells. Here, we report the surprising finding that in normal brain development, a substantial fraction of the lipids incorporated into central nervous system (CNS) myelin are contributed by astrocytes. The oligodendrocyte-specific inactivation of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP), an essential coactivator of the transcription factor SREBP and thus of lipid biosynthesis, resulted in significantly retarded CNS myelination; however, myelin appeared normal at 3 months of age. Importantly, embryonic deletion of the same gene in astrocytes, or in astrocytes and oligodendrocytes, caused a persistent hypomyelination, as did deletion from astrocytes during postnatal development. Moreover, when astroglial lipid synthesis was inhibited, oligodendrocytes began incorporating circulating lipids into myelin membranes. Indeed, a lipid-enriched diet was sufficient to rescue hypomyelination in these conditional mouse mutants. We conclude that lipid synthesis by oligodendrocytes is heavily supplemented by astrocytes in vivo and that horizontal lipid flux is a major feature of normal brain development and myelination.
A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin ...regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair.
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•miR-219 is critical for oligodendrocyte differentiation and myelination in murine CNS•miR-338 deletion exacerbates the dysmyelination phenotype in miR-219-deficient mice•miR-219 targets stage-specific inhibitors and Lingo1-Etv5 to promote CNS myelination•miR-219 mimics augment remyelination and functional recovery in demyelinating models
Wang et al. show that miR-219 collaborates with miR-338 and is required for proper oligodendrocyte differentiation and myelination in the mammalian CNS by targeting a network of stage-specific differentiation inhibitors, including Lingo1 and Etv5. Therapeutic delivery of miR-219 also enhances myelin repair in animal models of multiple sclerosis.
Metabolism and functions of lipids in myelin Schmitt, Sebastian; Cantuti Castelvetri, Ludovici; Simons, Mikael
Biochimica et biophysica acta,
August 2015, 2015-Aug, 2015-08-00, Letnik:
1851, Številka:
8
Journal Article
Recenzirano
Rapid conduction of nerve impulses requires coating of axons by myelin sheaths, which are lipid-rich and multilamellar membrane stacks. The lipid composition of myelin varies significantly from other ...biological membranes. Studies in mutant mice targeting various lipid biosynthesis pathways have shown that myelinating glia have a remarkable capacity to compensate the lack of individual lipids. However, compensation fails when it comes to maintaining long-term stability of myelin. Here, we summarize how lipids function in myelin biogenesis, axon-glia communication and in supporting long-term maintenance of myelin. We postulate that change in myelin lipid composition might be relevant for our understanding of aging and demyelinating diseases. This article is part of a Special Issue titled Brain Lipids.
•We highlight structural features and functions of the major myelin lipid species in myelin.•Myelinating glia have a remarkable capacity to compensate the lack of individual lipids.•Compensation fails when it comes to maintaining myelin long-term stability.
Effective and reliable encapsulation of phase change materials (PCMs) is essential and critical to the high‐performance solar‐thermal energy harvesting and storage. However, challenges remain ...pertaining to manufacturing scalability, high efficiency in energy storage/release, and anti‐leakage of melted PCMs. Herein, inspired by natural legume, a facile and scalable extrusion‐based core‐sheath 3D printing strategy is demonstrated for directly constructing bean‐pod‐structured octadecane (OD)/graphene (BOG) phase change microlattices, with regular porous configuration as well as individual and effective encapsulation of OD “beans” into highly interconnected graphene network wrapping layer built by closely stacked and aligned graphene sheets. The unique architectural features enable the ready spreading of light into the interior of phase change microlattice, a high transversal thermal conductivity of 1.67 W m−1 K−1, and rapid solar‐thermal energy harvesting and transfer, thereby delivering a high solar‐thermal energy storage efficiency, and a large phase change enthalpy of 190 J g−1 with 99.1% retention after 200 cycles. Most importantly, such encapsulated PCMs feature an exceptional thermal reliability and stability, with no leakage and shape variation even at 1000 thermal cycles and partial damage of BOG. This work validates the feasibility of scalably printing practical encapsulated PCMs, which may revolutionize the fabrication of composite PCMs for solar‐thermal energy storage devices.
Bean‐pod‐structured octadecane (OD)/graphene (BOG) phase change microlattices with individual and effective encapsulation of OD “beans” into highly interconnected graphene network wrapping layer, which are fabricated by extrusion‐based core‐sheath 3D printing strategy, feature an impressive solar‐thermal energy storage capacity with high efficiency and latent heat, as well as exceptional thermal reliability and stability.
Abstract
Background
We sought to determine the value of diffusion-weighted (DW) magnetic resonance imaging (MRI) for characterization of benign and malignant peripheral nerve sheath tumors (PNSTs) in ...patients with neurofibromatosis type 1 (NF1).
Methods
Twenty-six patients with NF1 and suspicion of malignant transformation of PNSTs were prospectively enrolled and underwent DW MRI at 3T. For a set of benign (n = 55) and malignant (n = 12) PNSTs, functional MRI parameters were derived from both biexponential intravoxel incoherent motion (diffusion coefficient D and perfusion fraction f) and monoexponential data analysis (apparent diffusion coefficients ADCs). A panel of morphological MRI features was evaluated using T1- and T2-weighted imaging. Mann–Whitney U-test, Fisher’s exact test, and receiver operating characteristic (ROC) analyses were applied to assess the diagnostic accuracy of quantitative and qualitative MRI. Cohen’s kappa was used to determine interrater reliability.
Results
Malignant PNSTs demonstrated significantly lower diffusivity (P < 0.0001) compared with benign PNSTs. The perfusion fraction f was significantly higher in malignant PNSTs (P < 0.001). In ROC analysis, functional MRI parameters showed high diagnostic accuracy for differentiation of PNSTs (eg, ADCmean, 92% sensitivity with 98% specificity, AUC 0.98; Dmean, 92% sensitivity with 98% specificity, AUC 0.98). By contrast, morphological imaging features had only limited sensitivity (18–94%) and specificity (18–82%) for identification of malignancy. Interrater reliability was higher for monoexponential data analysis.
Conclusion
DW imaging shows better diagnostic performance than morphological features and allows accurate differentiation of benign and malignant peripheral nerve sheath tumors in NF1.
Plexiform neurofibroma (PN) tumors are a hallmark manifestation of neurofibromatosis type 1 (NF1) that arise in the Schwann cell (SC) lineage. NF1 is a common heritable cancer predisposition syndrome ...caused by germline mutations in the NF1 tumor suppressor, which encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras proteins. Whereas most PN are clinically indolent, a subset progress to atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP) and/or to malignant peripheral nerve sheath tumors (MPNSTs). In small clinical series, loss of 9p21.3, which includes the CDKN2A locus, has been associated with the genesis of ANNUBP. Here we show that the Cdkn2a alternate reading frame (Arf) serves as a gatekeeper tumor suppressor in mice that prevents PN progression by inducing senescence-mediated growth arrest in aberrantly proliferating Nf1-/- SC. Conditional ablation of Nf1 and Arf in the neural crest-derived SC lineage allows escape from senescence, resulting in tumors that accurately phenocopy human ANNUBP and progress to MPNST with high penetrance. This animal model will serve as a platform to study the clonal development of ANNUBP and MPNST and to identify new therapies to treat existing tumors and to prevent disease progression.
Abstract The amyloid hypothesis (AH) of Alzheimer's disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (Aβ) in the brain. This hypothesis has been ...supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase Aβ production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including recent failures of clinical trials to impact dementia in humans even after successfully reducing Aβ deposits. Herein, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as late onset AD (LOAD). It regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits such as Aβ and tau as by-products of homeostatic myelin repair processes . It delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides “upstream” treatment targets. Such interventions could potentially treat multiple degenerative brain disorders by mitigating the effects of aging and associated changes in iron, cholesterol, and free radicals on oligodendrocytes and their myelin.
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