Myelin Maintenance Research Articles

Ermin is a p116RIP -interacting protein promoting oligodendroglial differentiation and myelin maintenance.

Myelin sheaths, which insulate the axons and ensure saltatory conduction of the nerve impulse, are generated and maintained via largely uncharacterized mechanisms. Ermin is an oligodendrocyte-specific protein associated with the cytoskeleton, but how it regulates cytoskeletal remodeling during oligodendrocyte differentiation and its role in myelin maintenance are not clear. To address this, we generated mice constitutively deficient for Ermn, the Ermin-coding gene. We found that aged Ermn-knockout mice exhibit an aberrant myelin architecture, with splitting of myelin layers, peeling of the myelin sheath from axons, and breakdown of myelinated fibers. As a result, these mice had remarkably impaired motor coordination. Ermn knockout also accelerated cuprizone-induced demyelination and exacerbated the associated movement disorders. Ermin was found to contribute to oligodendrocyte morphogenesis by associating with the myosin phosphatase Rho interacting protein (Mprip/p116RIP ) and inactivating RhoA, a GTPase that controls cytoskeletal rearrangement in differentiating cells. These findings provide novel insights into the mechanisms regulating oligodendroglial differentiation, the maintenance of the myelin sheaths, and remyelination.

Optimization of Propargylcholine to Label Newly Synthesized Myelin in the Rhesus Monkey Brain

Neuropathology in monkey and human brains often involves loss or damage to myelin and is a major factor impacting normal function as myelin constitutes 35%–40% of the forebrain. Methods to assess alterations in myelin include electron microscopy, histological stains (e.g. Luxol Fast Blue), immunohistochemistry (e.g. for myelin basic protein) and a label free confocal method (SCoRe), as well as diffusion MRI. Each method has advantages but none offer a reliable, validated method to assess microscopic changes in myelin (synthesis or repair) across the entire forebrain from gray matter fascicles to subcortical white matter. Here we present preliminary data that newly synthesized myelin can be detected with in vivo administration of a choline analog, propargylcholine (P‐Cho), that is readily incorporated into all classes of choline phospholipids including major components of the myelin sheath, phosphatidylcholine and sphingomyelin. Importantly, since P‐Cho contains an alkyne moiety, it can be visualized post mortem by conjugation with a fluoro‐labeled azide using click chemistry and detection with confocal microscopy. P‐Cho can be administered by intraperitoneal injection where it enters the circulation and is incorporated into myelin, allowing detection and quantification of newly synthesized myelin. While previous research has demonstrated the use of P‐Cho for assessing remyelination in mice, its efficacy and safety in monkeys has yet to be explored. This is important for our monkey model of normal aging where age‐related myelin pathology accounts for cognitive deficits and for our studies of recovery after damage to the motor cortex. The ability to quantify myelin plasticity in both of these models could provide significant insight into myelin pathology, repair, and maintenance. To test this, we administered P‐Cho daily for 6 days via IP injections (3.5 – 4.0 mg/kg) to 6 young adult and 1 older adult monkey at different time points before euthanasia (1, 2 and 6 weeks). Frozen brain sections were cut, labeled with a fluorescent azide, and the sections evaluated for the presence and specificity of P‐Cho by co‐labeling the tissue with antibodies for axons (SMI‐312) and newly formed actively myelinating oligodendrocytes (BCAS1). Co‐localization of P‐Cho was also performed using confocal reflectance microscopy (SCoRe). Preliminary analyses suggest effective incorporation of P‐Cho into newly synthesized myelin within 1 week of dosing and sustained presence beyond 6 weeks. These results demonstrate a promising new method for investigating remyelination and white matter pathologies related to aging that could also be applied to studies of neurodegeneration, brain injury, and neurological diseases in an animal model highly translatable to humans.Support or Funding InformationNIH Grants R01‐AG062831, R01‐AG043640; R01‐AG042512; R21‐AG061678; R21‐NS111174, U01‐NS076474

Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα-mediated lipid metabolism.

Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.

Demyelinating polyneuropathy in goats lacking prion protein.

Studies in mice with ablation of Prnp, the gene that encodes the cellular prion protein (PrPC ), have led to the hypothesis that PrPC is important for peripheral nerve myelin maintenance. Here, we have used a nontransgenic animal model to put this idea to the test; namely, goats that, due to a naturally occurring nonsense mutation, lack PrPC . Teased nerve fiber preparation revealed a demyelinating pathology in goats without PrPC . Affected nerves were invaded by macrophages and T cells and displayed vacuolated fibers, shrunken axons, and onion bulbs. Peripheral nerve lipid composition was similar in young goats with or without PrPC , but markedly different between corresponding groups of adult goats, reflecting the progressive nature of the neuropathy. This is the first report of a subclinical demyelinating polyneuropathy caused by loss of PrPC function in a nontransgenic mammal.

Myelin breakdown favours Mycobacterium leprae survival in Schwann cells.

Leprosy neuropathy is a chronic degenerative infectious disorder of the peripheral nerve caused by the intracellular obligate pathogen Mycobacterium leprae (M. leprae). Among all nonneuronal cells that constitute the nerve, Schwann cells are remarkable in supporting M. leprae persistence intracellularly. Notably, the success of leprosy infection has been attributed to its ability in inducing the demyelination phenotype after contacting myelinated fibres. However, the exact role M. leprae plays during the ongoing process of myelin breakdown is entirely unknown. Here, we provided evidence showing an unexpected predilection of leprosy pathogen for degenerating myelin ovoids inside Schwann cells. In addition, M. leprae infection accelerated the rate of myelin breakdown and clearance leading to increased formation of lipid droplets, by modulating a set of regulatory genes involved in myelin maintenance, autophagy, and lipid storage. Remarkably, the blockage of myelin breakdown significantly reduced M. leprae content, demonstrating a new unpredictable role of myelin dismantling favouring M. leprae physiology. Collectively, our study provides novel evidence that may explain the demyelination phenotype as an evolutionarily conserved mechanism used by leprosy pathogen to persist longer in the peripheral nerve.

Hereditary Motor and Sensory Neuropathy: Charcot Marie Tooth disease

Charcot Mariet Tooth’s disease (ECMT) or hereditary sensory and motor neuropathy is the one of the most common group of degenerative disorders of the peripheral nervous system, related with a set of genetic alterations that changes the structure, formation and maintenance of myelin. It affects 1 out of 2500 people without considering the age, gender or ethnicity; its etiology is entirely genetic. According to the nerve conduction velocity it is classified in demyelinating or CMT1, axonal or CMT2 and intermediate the same that has the features of the two previous ones. ECMT in majority of cases it is a slowly progressive disease, presenting with characteristic signs of high instep, stork leg, atrophy and decreased muscle strength, altered perception of vibratory stimuli, distal beginning with proximal progression; arreflexia and alteration of march. The diagnosis is based on family history, clinical and physical examination, complemented by electromyography studies, to determine their classification. Genetic tests are taken, based on the type of suspected ECMT, and these will be used for family counseling. Nowadays there is no specific and curative treatment, that’s why support should be provided with physical and rehabilitation therapies, psychological, occupational, as well as an optimal pain control.

Cell Biology of Intracellular Adaptation of Mycobacterium leprae in the Peripheral Nervous System.

The mammalian nervous system is invaded by a number of intracellular bacterial pathogens which can establish and progress infection in susceptible individuals. Subsequent clinical manifestation is apparent with the impairment of the functional units of the nervous system, i.e., the neurons and the supporting glial cells that produce myelin sheaths around axons and provide trophic support to axons and neurons. Most of these neurotrophic bacteria display unique features, have coevolved with the functional sophistication of the nervous system cells, and have adapted remarkably to manipulate neural cell functions for their own advantage. Understanding how these bacterial pathogens establish intracellular adaptation by hijacking endogenous pathways in the nervous system, initiating myelin damage and axonal degeneration, and interfering with myelin maintenance provides new knowledge not only for developing strategies to combat neurodegenerative conditions induced by these pathogens but also for gaining novel insights into cellular and molecular pathways that regulate nervous system functions. Since the pathways hijacked by bacterial pathogens may also be associated with other neurodegenerative diseases, it is anticipated that detailing the mechanisms of bacterial manipulation of neural systems may shed light on common mechanisms, particularly of early disease events. This chapter details a classic example of neurodegeneration, that caused by Mycobacterium leprae, which primarily infects glial cells of the peripheral nervous system (Schwann cells), and how it targets and adapts intracellularly by reprogramming Schwann cells to stem cells/progenitor cells. We also discuss implications of this host cell reprogramming by leprosy bacilli as a model in a wider context.

Transgenic overexpression of polysialyltransferase ST8SiaIV under the control of a neuron-specific promoter does not affect brain development but impairs exploratory behavior.

A large body of the literature has demonstrated that the polysialic acid (polySia) modification of the neural cell adhesion molecule (NCAM) is a key regulator of cellular interactions during brain development, maintenance and plasticity. To properly fulfill these functions, polySia concentration has to be carefully controlled. This is done by the regulation of the expression of the two polySia-synthesizing enzymes ST8SiaII and ST8SiaIV. From this point of view we and others have demonstrated that downregulation of ST8SiaIV during oligodendrocyte differentiation is a prerequisite for efficient myelin formation and maintenance. Here, we addressed the question whether the prevention of polySia downregulation in neurons affects brain and particularly myelin development and functioning. For this purpose, we developed transgenic (tg) mouse lines overexpressing the polysialyltransferase ST8SiaIV in neurons. tg expression of ST8SiaIV prevented the postnatal downregulation of polySia, and most of the polySias in the forebrain and brain stem of adult tg mice were associated with NCAM-140 and NCAM-180 isoforms. Structural examination of the brain revealed no overt abnormalities of axons and myelin. In addition, ultrastructural and western blot analyses indicated normal myelin development. However, behavioral studies revealed reduced rearing activity, a measure for exploratory behavior, while parameters of motor activity were not affected in tg mice. Taken together, these results suggest that a persisting presence of polySia in neurons has no major effect on brain structure, myelination and myelin maintenance, but causes mild behavioral changes.

Chromatin remodeler Ep400 ensures oligodendrocyte survival and is required for myelination in the vertebrate central nervous system.

Differentiating oligodendrocytes generate myelin to ensure rapid saltatory conduction in the vertebrate central nervous system. Although oligodendroglial differentiation and myelination are accompanied by dramatic chromatin reorganizations, previously studied chromatin remodelers had only limited direct effects on the process. To study the functional significance of chromatin changes for myelination and identify relevant remodelers, we deleted Ep400, the central ATP-hydrolyzing subunit of the TIP60/EP400 complex, at defined times of mouse oligodendrocyte development. Whereas Ep400-deficient oligodendrocyte precursors develop normally, terminal differentiation and myelination are dramatically impaired. Mechanistically, Ep400 interacts with transcription factor Sox10, binds to regulatory regions of the Myrf gene and is required to induce this central transcriptional regulator of the myelination program. In addition to reduced and aberrant myelin formation, oligodendrocytes exhibit increased DNA damage and apoptosis so that numbers never reach wildtype levels during the short lifespan of Ep400-deficient mice. Ep400 deletion in already mature oligodendrocytes remains phenotypically inapparent arguing that Ep400 is dispensable for myelin maintenance. Given its essential function in myelin formation, modulation of Ep400 activity may be beneficial in conditions such as multiple sclerosis where this process is compromised.

Membrane Protein Identification in Rodent Brain Tissue Samples and Acute Brain Slices.

Acute brain slices are a sample format for electrophysiology, disease modeling, and organotypic cultures. Proteome analyses based on mass spectrometric measurements are seldom used on acute slices, although they offer high-content protein analyses and explorative approaches. In neuroscience, membrane proteins are of special interest for proteome-based analysis as they are necessary for metabolic, electrical, and signaling functions, including myelin maintenance and regeneration. A previously published protocol for the enrichment of plasma membrane proteins based on aqueous two-phase polymer systems followed by mass spectrometric protein identification was adjusted to the small sample size of single acute murine slices from newborn animals and the reproducibility of the results was analyzed. For this, plasma membrane proteins of 12 acute slice samples from six animals were enriched and analyzed by liquid chromatography-mass spectrometry. A total of 1161 proteins were identified, of which 369 were assigned to membranes. Protein abundances showed high reproducibility between samples. The plasma membrane protein separation protocol can be applied to single acute slices despite the low sample size and offers a high yield of identifiable proteins. This is not only the prerequisite for proteome analysis of organotypic slice cultures but also allows for the analysis of small-sized isolated brain regions at the proteome level.

Schwann cells ER-associated degradation contributes to myelin maintenance in adult nerves and limits demyelination in CMT1B mice.

In the peripheral nervous system (PNS) myelinating Schwann cells synthesize large amounts of myelin protein zero (P0) glycoprotein, an abundant component of peripheral nerve myelin. In humans, mutations in P0 cause the demyelinating Charcot-Marie-Tooth 1B (CMT1B) neuropathy, one of the most diffused genetic disorders of the PNS. We previously showed that several mutations, such as the deletion of serine 63 (P0-S63del), result in misfolding and accumulation of P0 in the endoplasmic reticulum (ER), with activation of the unfolded protein response (UPR). In addition, we observed that S63del mouse nerves display the upregulation of many ER-associated degradation (ERAD) genes, suggesting a possible involvement of this pathway in the clearance of the mutant P0. In ERAD in fact, misfolded proteins are dislocated from the ER and targeted for proteasomal degradation. Taking advantage of inducible cells that express the ER retained P0, here we show that the P0-S63del glycoprotein is degraded via ERAD. Moreover, we provide strong evidence that the Schwann cell-specific ablation of the ERAD factor Derlin-2 in S63del nerves exacerbates both the myelin defects and the UPR in vivo, unveiling a protective role for ERAD in CMT1B neuropathy. We also found that lack of Derlin-2 affects adult myelin maintenance in normal nerves, without compromising their development, pinpointing ERAD as a previously unrecognized player in preserving Schwann cells homeostasis in adulthood. Finally, we provide evidence that treatment of S63del peripheral nerve cultures with N-Acetyl-D-Glucosamine (GlcNAc), known to enhance protein quality control pathways in C.elegans, ameliorates S63del nerve myelination ex vivo. Overall, our study suggests that potentiating adaptive ER quality control pathways might represent an appealing strategy to treat both conformational and age-related PNS disorders.

Age-related glial cell heterogeneity

Neuroscience Oligodendrocyte progenitor cells are widely distributed throughout the adult brain and are the main proliferative cell. As they mature into oligodendrocytes, they produce myelin; however, their composition and function in the adult brain are unclear and controversial. Using whole-cell patch-clamp recordings, Spitzer et al. looked at how the functional properties of oligodendrocytes change with developmental milestones and brain location. Early in life, oligodendrocyte progenitor cells form a homogeneous population, but during development, they acquire several different ion channels and become functionally heterogeneous. The resulting differences in electrophysiological properties underlie functional differentiation into activities such as motor learning and myelin maintenance. Neuron 101 , 459 (2019).

Lysosomal Leukodystrophies Lysosomal Storage Diseases Associated With White Matter Abnormalities.

The leukodystrophies are a group of genetic metabolic diseases characterized by an abnormal development or progressive degeneration of the myelin sheath. The myelin is a complex sheath composed of several macromolecules covering axons as an insulator. Each of the leukodystrophies is caused by mutations in genes encoding enzymes that are involved in myelin production and maintenance. The lysosomal storage diseases are inborn disorders of compartmentalized cellular organelles with broad clinical manifestations secondary to the progressive accumulation of undegraded macromolecules within lysosomes and related organelles. The more than 60 different lysosomal storage diseases are rare diseases; however, collectively, the incidence of lysosomal storage diseases ranges just over 1 in 2500 live births. The majority of lysosomal storage diseases are associated with neurologic manifestations including developmental delay, seizures, acroparesthesia, motor weakness, and extrapyramidal signs. These inborn organelle disorders show wide clinical variability affecting individuals from all age groups. In addition, several of neurologic, also known as neuronopathic, lysosomal storage diseases are associated with some level of white matter disease, which often triggers the diagnostic investigation. Most lysosomal storage diseases are autosomal recessively inherited and few are X-linked, with females being at risk of presenting with mild, but clinically relevant neurologic manifestations. Biochemical assays are the basis of the diagnosis and are usually confirmed by molecular genetic testing. Novel therapies have emerged. However, most affected patients with lysosomal storage diseases have only supportive management to rely on. A better understanding of the mechanisms resulting in the leukodystrophy will certainly result in innovative and efficacious disease-modifying therapies.

Regulation of Myelination by Exosome Associated Retinoic Acid Release from NG2-Positive Cells.

In the CNS, oligodendrocytes are responsible for myelin formation and maintenance. Following spinal cord injury, oligodendrocyte loss and an inhibitory milieu compromise remyelination and recovery. Here, we explored the role of retinoic acid receptor-beta (RARβ) signaling in remyelination. Using a male Sprague Dawley rat model of PNS-CNS injury, we show that oral treatment with a novel drug like RARβ agonist, C286, induces neuronal expression of the proteoglycan decorin and promotes myelination and differentiation of oligodendrocyte precursor cells (NG2+ cells) in a decorin-mediated neuron–glia cross talk. Decorin promoted the activation of RARα in NG2+ cells by increasing the availability of the endogenous ligand RA. NG2+ cells synthesize RA, which is released in association with exosomes. We found that decorin prevents this secretion through regulation of the EGFR–calcium pathway. Using functional and pharmacological studies, we further show that RARα signaling is both required and sufficient for oligodendrocyte differentiation. These findings illustrate that RARβ and RARα are important regulators of oligodendrocyte differentiation, providing new targets for myelination.SIGNIFICANCE STATEMENT This study identifies novel therapeutic targets for remyelination after PNS-CNS injury. Pharmacological and knock-down experiments show that the retinoic acid (RA) signaling promotes differentiation of oligodendrocyte precursor cells (OPCs) and remyelination in a cross talk between neuronal RA receptor-beta (RARβ) and RARα in NG2+ cells. We show that stimulation of RARα is required for the differentiation of OPCs and we describe for the first time how oral treatment with a RARβ agonist (C286, currently being tested in a Phase 1 trial, ISRCTN12424734) leads to the endogenous synthesis of RA through retinaldehyde dehydrogenase 2 (Raldh2) in NG2 cells and controls exosome-associated-RA intracellular levels through a decorin–Ca2+ pathway. Although RARβ has been implicated in distinct aspects of CNS regeneration, this study identifies a novel function for both RARβ and RARα in remyelination.

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.

Pelizaeus-Merzbacher Disease: Molecular and Cellular Pathologies and Associated Phenotypes.

Pelizaeus-Merzbacher disease (PMD) represents a group of disorders known as hypomyelinating leukodystrophies, which are characterized by abnormal development and maintenance of myelin in the central nervous system. PMD is caused by different types of mutations in the proteolipid protein 1 (PLP1) gene, which encodes a major myelin membrane lipoprotein. These mutations in the PLP1 gene result in distinct cellular and molecular pathologies and a spectrum of clinical phenotypes. In this chapter, I discuss the historical aspects and current understanding of the mechanisms underlying how different PLP1 mutations disrupt the normal process of myelination and result in PMD and other disorders.

Proteomic approach underlying the hippocampal neurodegeneration caused by low doses of methylmercury after long-term exposure in adult rats.

Methylmercury (MeHg) is an important toxicant that causes cognitive dysfunctions in humans. This study aimed to investigate the proteomic and biochemical alterations of the hippocampus associated with behavioural consequences of low doses of MeHg in a long-term exposure model, and to realistically mimic in vivo the result of human exposure to this toxicant. Adult Wistar male rats were exposed to a dose of MeHg at 0.04 mg kg-1 day-1 by gavage for 60 days. Total mercury (Hg) content was significantly increased in the hippocampal parenchyma. The increase in the Hg levels was capable of reducing neuron and astrocyte cell density in the CA1, CA3, hilus and dentate gyrus regions, increasing both malondialdehyde and nitrite levels and decreasing antioxidant capacity against peroxyl radicals. The proteomic analysis detected 1041 proteins with altered expression due to MeHg exposure, including 364 proteins with no expression, 295 proteins with de novo expression and 382 proteins with up- or down-regulated expression. This proteomic approach revealed alterations in pathways related to chemical synapses, metabolism, amino acid transport, cell energy, neurodegenerative processes and myelin maintenance. Therefore, even at low doses of MeHg exposure, it is possible to cause hippocampal damage in adult rats at many organisational levels, triggering oxidative stress and proteome misbalance, featuring a neurodegenerative process and culminating in long- and short-term memory and learning deficits.

Apolipoprotein serum levels related to metabolic side effects in patients with schizophrenia

In the general population, metabolic syndrome (MetS) is associated with a 4 times relative risk of developing diabetes and approximately a 2-fold risk of coronary heart disease, stroke, and premature mortality [1]. In patients with schizophrenia the overall rate of MetS is 32.5% [1]. This contributes to having an average mortality rate that is 2-3 times higher than the general population, corresponding to a 10-25 year shortened life expectancy [2]. Antipsychotics are associated with an increased risk for several physical diseases, including obesity, dyslipidemia, diabetes mellitus [2,3]. Use both of classical conventional and modern atypical neuroleptics have been associated with metabolic disturbances; so drug-induced metabolic disturbances are observed in 39.0% of patients taking haloperidol, 44.0% - clozapine, 22.0% - aripiprazole, 33.3% - amisulpride, 34.0% - olanzapine, 35.0% – risperidone [4]. Therefore, an ongoing need exists for reliable predictors of metabolic risks in individual patients indicated for antipsychotic treatment. Apolipoproteins and cholesterol play a critical role in synapse and myelin maintenance as well as integrity and may thus be both appealing candidates in the pathogenesis of schizophrenia and biomarkers of antipsychotic induce side metabolic effects [5]. The aim of this study is to investigate serum apolipoproteins concentration in schizophrenic patients with or without metabolic syndrome and healthy donors. Methods: The study was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. After obtaining approval of the study protocol by the local ethical committee, suitable participants were recruited from psychiatric hospitals. We included 53 patients with diagnosis of paranoid schizophrenia verified according to the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10: F20). Patients have been divided into two groups with and without MetS according to criteria the International Diabetes Federation (2005). All patients received antipsychotic treatment. The control group included 20 mentally and physically healthy subjects. Serum apolipoproteins A1, C3, E, A2 and C2 were measured using xMAP technology (Luminex). Statistical analysis was performed by SPSS version 20.0. Results: We found a significant decrease in the concentration of apolipoprotein A1 in the serum of schizophrenic patients with a MetS (p = 0.002) and no side effects (p = 0.013) compared with the control group. The level of ApoC3 (p = 0.001) and ApoC2 (p = 0.002) were increased in patients with schizophrenia with MetS in comparison with the control group and patients without MetS. No other significant differences were established concerning the other assayed apolipoproteins. Conclusions: Literature date and our results suggest that disturbances in level of Apo A1 play role in pathogenesis of schizophrenia while level of ApoC3 and ApoC2 can reflect the metabolic disbalance and could be a novel biomarker to predict metabolic side effects associated with antipsychotic treatment. Future studies with a larger sample size, a well-defined control group, a longer study time duration could be of great clinical utility, when these can predict antipsychotic-associated metabolic problems in patients that carry a higher cardiovascular risk. Disclosure statement: This work is supported by RSF grant N 18-15-00011

Evolvability of the actin cytoskeleton in oligodendrocytes during central nervous system development and aging.

The organization of actin filaments into a wide range of subcellular structures is a defining feature of cell shape and dynamics, important for tissue development and homeostasis. Nervous system function requires morphological and functional plasticity of neurons and glial cells, which is largely determined by the dynamic reorganization of the actin cytoskeleton in response to intrinsic and extracellular signals. Oligodendrocytes are specialized glia that extend multiple actin-based protrusions to form the multilayered myelin membrane that spirally wraps around axons, increasing conduction speed and promoting long-term axonal integrity. Myelination is a remarkable biological paradigm in development, and maintenance of myelin is essential for a healthy adult nervous system. In this review, we discuss how structure and dynamics of the actin cytoskeleton is a defining feature of myelinating oligodendrocytes' biology and function. We also review "old and new" concepts to reflect on the potential role of the cytoskeleton in balancing life and death of myelin membranes and oligodendrocytes in the aging central nervous system.

The miRNA biogenesis pathway prevents inappropriate expression of injury response genes in developing and adult Schwann cells.

Proper function of the nervous system depends on myelination. In peripheral nerves, Schwann cells (SCs) myelinate axons and the miRNA biogenesis pathway is required for developmental myelination and myelin maintenance. However, regulatory roles of this pathway at different stages of myelination are only partially understood. We addressed the requirement of the core miRNA biogenesis pathway components Dgcr8, Drosha, and Dicer in developing and adult SCs using mouse mutants with a comparative genetics and transcriptomics approach. We found that the microprocessor components Dgcr8 and Drosha are crucial for axonal radial sorting and to establish correct SC numbers upon myelination. Transcriptome analyses revealed a requirement of the microprocessor to prevent aberrantly increased expression of injury‐response genes. Those genes are predicted targets of abundant miRNAs in sciatic nerves (SNs) during developmental myelination. In agreement, Dgcr8 and Dicer are required for proper maintenance of the myelinated SC state, where abundant miRNAs in adult SNs are predicted to target injury‐response genes. We conclude that the miRNA biogenesis pathway in SCs is crucial for preventing inappropriate activity of injury‐response genes in developing and adult SCs.