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Oligodendrocyte Physiology and Pathology Function
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Oligodendrocyte Physiology and Pathology Function

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cells of the Nervous System".

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A printed edition of this Special Issue is available here.

Editor

Prof. Dr. Markus Kipp

E-Mail Website
Collection Editor
Department of Anatomy, Rostock University Medical Center, 18055 Rostock, Germany
Interests: neurobiology; neuroscience; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

In multiple sclerosis (MS) patients, chronic clinical deficits are known to result from axonal degeneration, which is triggered by demyelination and inadequate remyelination. The underlying mechanisms of oligodendrocyte degeneration and regeneration are still poorly understood. This Topical Collection will collect articles that address ongoing research into promoting myelin repair, understanding the physiology and pathology of oligodendrocytes, the interaction of oligodendrocytes with central and peripheral immune cells, and the various models that allow us to study oligodendrocyte physiology and pathology.

Prof. Markus Kipp
Collection Editor

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Keywords

  • Demyelination
  • Remyelination
  • Neurodegeneration
  • Oligodendrocyte
  • Myelin
  • Multiple sclerosis
  • Leukodystrophy
  • Cell–cell communication.

Published Papers (25 papers)

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2023

Jump to: 2022, 2020, 2019

19 pages, 4614 KiB  
Article
Metabolomics Profile of the Secretome of Space-Flown Oligodendrocytes
by Laurent Vergnes, Bernard Foucaud, Carlos Cepeda and Araceli Espinosa-Jeffrey
Cells 2023, 12(18), 2249; https://doi.org/10.3390/cells12182249 - 11 Sep 2023
Cited by 2 | Viewed by 1023
Abstract
Intracranial hypertension (ICP) and visual impairment intracranial pressure (VIIP) are some of the sequels of long-term space missions. Here we sought to determine how space microgravity (µG) impacts the metabolomics profile of oligodendrocyte progenitors (OLPs), the myelin-forming cells in the central nervous system. [...] Read more.
Intracranial hypertension (ICP) and visual impairment intracranial pressure (VIIP) are some of the sequels of long-term space missions. Here we sought to determine how space microgravity (µG) impacts the metabolomics profile of oligodendrocyte progenitors (OLPs), the myelin-forming cells in the central nervous system. We report increased glutamate and energy metabolism while the OLPs were in space for 26 days. We also show that after space flight, OLPs (SPC OLPs) display significantly increased mitochondrial respiration and glycolysis. These data are in agreement with our previous work using simulated microgravity. In addition, our global metabolomics approach allowed for the discovery of endogenous metabolites secreted by OLPs while in space that are significantly modulated by microgravity. Our results provide, for the first time, relevant information about the energetic state of OLPs while in space and after space flight. The functional and molecular relevance of these specific pathways are promising targets for therapeutic intervention for humans in long-term space missions to the moon, Mars and beyond. Full article
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14 pages, 3313 KiB  
Article
Promoting the Differentiation of Neural Progenitor Cells into Oligodendrocytes through the Induction of Olig2 Expression: A Transcriptomic Study Using RNA-seq Analysis
by Katarzyna Pieczonka, Mohamad Khazaei and Michael G. Fehlings
Cells 2023, 12(9), 1252; https://doi.org/10.3390/cells12091252 - 26 Apr 2023
Cited by 2 | Viewed by 1895
Abstract
Oligodendrocytes are the myelinating cells of the central nervous system that facilitate efficient signal transduction. The loss of these cells and the associated myelin sheath can lead to profound functional deficits. Moreover, oligodendrocytes also play key roles in mediating glial-neuronal interactions, which further [...] Read more.
Oligodendrocytes are the myelinating cells of the central nervous system that facilitate efficient signal transduction. The loss of these cells and the associated myelin sheath can lead to profound functional deficits. Moreover, oligodendrocytes also play key roles in mediating glial-neuronal interactions, which further speaks to their importance in health and disease. Neural progenitor cells (NPCs) are a promising source of cells for the treatment of oligodendrocyte-related neurological diseases due to their ability to differentiate into a variety of cell types, including oligodendrocytes. However, the efficiency of oligodendrocyte differentiation is often low. In this study, we induced the expression of the Olig2 transcription factor in tripotent NPCs using a doxycycline-inducible promoter, such that the extent of oligodendrocyte differentiation could be carefully regulated. We characterized the differentiation profile and the transcriptome of these inducible oligodendrogenic NPCs (ioNPCs) using a combination of qRT-PCR, immunocytochemistry and RNA sequencing with gene ontology (GO) and gene set enrichment analysis (GSEA). Our results show that the ioNPCs differentiated into a significantly greater proportion of oligodendrocytes than the NPCs. The induction of Olig2 expression was also associated with the upregulation of genes involved in oligodendrocyte development and function, as well as the downregulation of genes involved in other cell lineages. The GO and GSEA analyses further corroborated the oligodendrocyte specification of the ioNPCs. Full article
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2022

Jump to: 2023, 2020, 2019

12 pages, 933 KiB  
Review
Insights into White Matter Defect in Huntington’s Disease
by Yize Sun, Huichun Tong, Tianqi Yang, Li Liu, Xiao-Jiang Li and Shihua Li
Cells 2022, 11(21), 3381; https://doi.org/10.3390/cells11213381 - 26 Oct 2022
Cited by 5 | Viewed by 1837
Abstract
Huntington’s disease (HD) is an autosomal-dominant inherited progressive neurodegenerative disorder. It is caused by a CAG repeat expansion in the Huntingtin gene that is translated to an expanded polyglutamine (PolyQ) repeat in huntingtin protein. HD is characterized by mood swings, involuntary movement, and [...] Read more.
Huntington’s disease (HD) is an autosomal-dominant inherited progressive neurodegenerative disorder. It is caused by a CAG repeat expansion in the Huntingtin gene that is translated to an expanded polyglutamine (PolyQ) repeat in huntingtin protein. HD is characterized by mood swings, involuntary movement, and cognitive decline in the late disease stage. HD patients often die 15–20 years after disease onset. Currently, there is no cure for HD. Due to the striking neuronal loss in HD, most studies focused on the investigation of the predominantly neuronal degeneration in specific brain regions. However, the pathology of the white matter area in the brains of HD patients was also reported by clinical imaging studies, which showed white matter abnormalities even before the clinical onset of HD. Since oligodendrocytes form myelin sheaths around the axons in the brain, white matter lesions are likely attributed to alterations in myelin and oligodendrocyte-associated changes in HD. In this review, we summarized the evidence for white matter, myelin, and oligodendrocytes alterations that were previously observed in HD patients and animal models. We also discussed potential mechanisms for white matter changes and possible treatment to prevent glial dysfunction in HD. Full article
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15 pages, 2153 KiB  
Article
Decreased Oligodendrocyte Number in Hippocampal Subfield CA4 in Schizophrenia: A Replication Study
by Andrea Schmitt, Laura Tatsch, Alisa Vollhardt, Thomas Schneider-Axmann, Florian J. Raabe, Lukas Roell, Helmut Heinsen, Patrick R. Hof, Peter Falkai and Christoph Schmitz
Cells 2022, 11(20), 3242; https://doi.org/10.3390/cells11203242 - 15 Oct 2022
Cited by 9 | Viewed by 2375
Abstract
Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we [...] Read more.
Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we reported a reduction in oligodendrocyte number in CA4 in schizophrenia and of granular neurons in the dentate gyrus (DG). Here, we aimed to replicate these findings in an independent sample. We used a stereological approach to investigate the numbers and densities of neurons, oligodendrocytes, and astrocytes in CA4 and of granular neurons in the DG of left and right hemispheres in 11 brains from men with schizophrenia and 11 brains from age- and sex-matched healthy controls. In schizophrenia, a decreased number and density of oligodendrocytes was detected in the left and right CA4, whereas mean volumes of CA4 and the DG and the numbers and density of neurons, astrocytes, and granular neurons were not different in patients and controls, even after adjustment of variables because of positive correlations with postmortem interval and age. Our results replicate the previously described decrease in oligodendrocytes bilaterally in CA4 in schizophrenia and point to a deficit in oligodendrocyte maturation or a loss of mature oligodendrocytes. These changes result in impaired myelination and neuronal decoupling, both of which are linked to altered functional connectivity and subsequent cognitive dysfunction in schizophrenia. Full article
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20 pages, 4413 KiB  
Article
Rewiring of Glucose and Lipid Metabolism Induced by G Protein-Coupled Receptor 17 Silencing Enables the Transition of Oligodendrocyte Progenitors to Myelinating Cells
by Davide Marangon, Matteo Audano, Silvia Pedretti, Marta Fumagalli, Nico Mitro, Davide Lecca, Donatella Caruso and Maria P. Abbracchio
Cells 2022, 11(15), 2369; https://doi.org/10.3390/cells11152369 - 02 Aug 2022
Cited by 4 | Viewed by 3132
Abstract
In the mature central nervous system (CNS), oligodendrocytes (OLs) provide support and insulation to axons thanks to the production of a myelin sheath. During their maturation to myelinating cells, OLs require energy and building blocks for lipids, which implies a great investment of [...] Read more.
In the mature central nervous system (CNS), oligodendrocytes (OLs) provide support and insulation to axons thanks to the production of a myelin sheath. During their maturation to myelinating cells, OLs require energy and building blocks for lipids, which implies a great investment of energy fuels and molecular sources of carbon. The oligodendroglial G protein-coupled receptor 17 (GPR17) has emerged as a key player in OL maturation; it reaches maximal expression in pre-OLs, but then it has to be internalized to allow terminal maturation. In this study, we aim at elucidating the role of physiological GPR17 downregulation in OL metabolism by applying transcriptomics, metabolomics and lipidomics on differentiating OLs. After GPR17 silencing, we found a significant increase in mature OL markers and alteration of several genes involved in glucose metabolism and lipid biosynthesis. We also observed an increased release of lactate, which is partially responsible for the maturation boost induced by GPR17 downregulation. Concomitantly, GPR17 depletion also changed the kinetics of specific myelin lipid classes. Globally, this study unveils a functional link between GPR17 expression, lactate release and myelin composition, and suggests that innovative interventions targeting GPR17 may help to foster endogenous myelination in demyelinating diseases. Full article
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27 pages, 4751 KiB  
Article
The Extracellular Matrix Proteins Tenascin-C and Tenascin-R Retard Oligodendrocyte Precursor Maturation and Myelin Regeneration in a Cuprizone-Induced Long-Term Demyelination Animal Model
by Juliane Bauch and Andreas Faissner
Cells 2022, 11(11), 1773; https://doi.org/10.3390/cells11111773 - 28 May 2022
Cited by 8 | Viewed by 3822
Abstract
Oligodendrocytes are the myelinating cells of the central nervous system. The physiological importance of oligodendrocytes is highlighted by diseases such as multiple sclerosis, in which the myelin sheaths are degraded and the axonal signal transmission is compromised. In a healthy brain, spontaneous remyelination [...] Read more.
Oligodendrocytes are the myelinating cells of the central nervous system. The physiological importance of oligodendrocytes is highlighted by diseases such as multiple sclerosis, in which the myelin sheaths are degraded and the axonal signal transmission is compromised. In a healthy brain, spontaneous remyelination is rare, and newly formed myelin sheaths are thinner and shorter than the former ones. The myelination process requires the migration, proliferation, and differentiation of oligodendrocyte precursor cells (OPCs) and is influenced by proteins of the extracellular matrix (ECM), which consists of a network of glycoproteins and proteoglycans. In particular, the glycoprotein tenascin-C (Tnc) has an inhibitory effect on the differentiation of OPCs and the remyelination efficiency of oligodendrocytes. The structurally similar tenascin-R (Tnr) exerts an inhibitory influence on the formation of myelin membranes in vitro. When Tnc knockout oligodendrocytes were applied to an in vitro myelination assay using artificial fibers, a higher number of sheaths per single cell were obtained compared to the wild-type control. This effect was enhanced by adding brain-derived neurotrophic factor (BDNF) to the culture system. Tnr−/− oligodendrocytes behaved differently in that the number of formed sheaths per single cell was decreased, indicating that Tnr supports the differentiation of OPCs. In order to study the functions of tenascin proteins in vivo Tnc−/− and Tnr−/− mice were exposed to Cuprizone-induced demyelination for a period of 10 weeks. Both Tnc−/− and Tnr−/− mouse knockout lines displayed a significant increase in the regenerating myelin sheath thickness after Cuprizone treatment. Furthermore, in the absence of either tenascin, the number of OPCs was increased. These results suggest that the fine-tuning of myelin regeneration is regulated by the major tenascin proteins of the CNS. Full article
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12 pages, 3219 KiB  
Article
Different Methods for Evaluating Microglial Activation Using Anti-Ionized Calcium-Binding Adaptor Protein-1 Immunohistochemistry in the Cuprizone Model
by Mariela Wittekindt, Hannes Kaddatz, Sarah Joost, Anna Staffeld, Yamen Bitar, Markus Kipp and Linda Frintrop
Cells 2022, 11(11), 1723; https://doi.org/10.3390/cells11111723 - 24 May 2022
Cited by 16 | Viewed by 2883
Abstract
Microglia play an important role in the pathology of various central nervous system disorders, including multiple sclerosis (MS). While different methods exist to evaluate the extent of microglia activation, comparative studies investigating the sensitivity of these methods are missing for most models. In [...] Read more.
Microglia play an important role in the pathology of various central nervous system disorders, including multiple sclerosis (MS). While different methods exist to evaluate the extent of microglia activation, comparative studies investigating the sensitivity of these methods are missing for most models. In this study, we systematically evaluated which of the three commonly used histological methods (id est, quantification of microglia density, densitometrically evaluated staining intensity, or cellular morphology based on the determination of a ramification index, all measured in anti-ionized calcium-binding adaptor protein-1 (IBA1) immunohistochemical stains) is the most sensitive method to detect subtle changes in the microglia activation status in the context of MS. To this end, we used the toxin-induced cuprizone model which allows the experimental induction of a highly reproducible demyelination in several central nervous system regions, paralleled by early microglia activation. In this study, we showed that after 3 weeks of cuprizone intoxication, all methods reveal a significant microglia activation in the white matter corpus callosum. In contrast, in the affected neocortical grey matter, the evaluation of anti-IBA1 cell morphologies was the most sensitive method to detect subtle changes of microglial activation. The results of this study provide a useful guide for future immunohistochemical evaluations in the cuprizone and other neurodegenerative models. Full article
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2020

Jump to: 2023, 2022, 2019

5 pages, 198 KiB  
Editorial
Oligodendrocyte Physiology and Pathology Function
by Markus Kipp
Cells 2020, 9(9), 2078; https://doi.org/10.3390/cells9092078 - 11 Sep 2020
Cited by 14 | Viewed by 3076
Abstract
The adult vertebrate central nervous system (CNS) mainly consists of neurons, astrocytes, microglia cells and oligodendrocytes [...] Full article
18 pages, 17818 KiB  
Article
Delayed Demyelination and Impaired Remyelination in Aged Mice in the Cuprizone Model
by Stefan Gingele, Florian Henkel, Sandra Heckers, Thiemo M. Moellenkamp, Martin W. Hümmert, Thomas Skripuletz, Martin Stangel and Viktoria Gudi
Cells 2020, 9(4), 945; https://doi.org/10.3390/cells9040945 - 11 Apr 2020
Cited by 24 | Viewed by 5026
Abstract
To unravel the failure of remyelination in multiple sclerosis (MS) and to test promising remyelinating treatments, suitable animal models like the well-established cuprizone model are required. However, this model is only standardized in young mice. This does not represent the typical age of [...] Read more.
To unravel the failure of remyelination in multiple sclerosis (MS) and to test promising remyelinating treatments, suitable animal models like the well-established cuprizone model are required. However, this model is only standardized in young mice. This does not represent the typical age of MS patients. Furthermore, remyelination is very fast in young mice, hindering the examination of effects of remyelination-promoting agents. Thus, there is the need for a better animal model to study remyelination. We therefore aimed to establish the cuprizone model in aged mice. 6-month-old C57BL6 mice were fed with different concentrations of cuprizone (0.2–0.6%) for 5–6.5 weeks. De- and remyelination in the medial and lateral parts of the corpus callosum were analyzed by immunohistochemistry. Feeding aged mice 0.4% cuprizone for 6.5 weeks resulted in the best and most reliable administration scheme with virtually complete demyelination of the corpus callosum. This was accompanied by a strong accumulation of microglia and near absolute loss of mature oligodendrocytes. Subsequent remyelination was initially robust but remained incomplete. The remyelination process in mature adult mice better represents the age of MS patients and offers a better model for the examination of regenerative therapies. Full article
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21 pages, 504 KiB  
Review
Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System
by Erik Nutma, Démi van Gent, Sandra Amor and Laura A. N. Peferoen
Cells 2020, 9(3), 600; https://doi.org/10.3390/cells9030600 - 03 Mar 2020
Cited by 96 | Viewed by 13844
Abstract
Over the last decade knowledge of the role of astrocytes in central nervous system (CNS) neuroinflammatory diseases has changed dramatically. Rather than playing a merely passive role in response to damage it is clear that astrocytes actively maintain CNS homeostasis by influencing pH, [...] Read more.
Over the last decade knowledge of the role of astrocytes in central nervous system (CNS) neuroinflammatory diseases has changed dramatically. Rather than playing a merely passive role in response to damage it is clear that astrocytes actively maintain CNS homeostasis by influencing pH, ion and water balance, the plasticity of neurotransmitters and synapses, cerebral blood flow, and are important immune cells. During disease astrocytes become reactive and hypertrophic, a response that was long considered to be pathogenic. However, recent studies reveal that astrocytes also have a strong tissue regenerative role. Whilst most astrocyte research focuses on modulating neuronal function and synaptic transmission little is known about the cross-talk between astrocytes and oligodendrocytes, the myelinating cells of the CNS. This communication occurs via direct cell-cell contact as well as via secreted cytokines, chemokines, exosomes, and signalling molecules. Additionally, this cross-talk is important for glial development, triggering disease onset and progression, as well as stimulating regeneration and repair. Its critical role in homeostasis is most evident when this communication fails. Here, we review emerging evidence of astrocyte-oligodendrocyte communication in health and disease. Understanding the pathways involved in this cross-talk will reveal important insights into the pathogenesis and treatment of CNS diseases. Full article
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2019

Jump to: 2023, 2022, 2020

13 pages, 9614 KiB  
Article
Investigation of Cuprizone-Induced Demyelination in mGFAP-Driven Conditional Transient Receptor Potential Ankyrin 1 (TRPA1) Receptor Knockout Mice
by Gábor Kriszta, Balázs Nemes, Zoltán Sándor, Péter Ács, Sámuel Komoly, Zoltán Berente, Kata Bölcskei and Erika Pintér
Cells 2020, 9(1), 81; https://doi.org/10.3390/cells9010081 - 28 Dec 2019
Cited by 13 | Viewed by 3295
Abstract
Transient receptor potential ankyrin 1 (TRPA1) receptors are non-selective cation channels responsive to a variety of exogenous irritants and endogenous stimuli including products of oxidative stress. It is mainly expressed by primary sensory neurons; however, expression of TRPA1 by astrocytes and oligodendrocytes has [...] Read more.
Transient receptor potential ankyrin 1 (TRPA1) receptors are non-selective cation channels responsive to a variety of exogenous irritants and endogenous stimuli including products of oxidative stress. It is mainly expressed by primary sensory neurons; however, expression of TRPA1 by astrocytes and oligodendrocytes has recently been detected in the mouse brain. Genetic deletion of TRPA1 was shown to attenuate cuprizone-induced oligodendrocyte apoptosis and myelin loss in mice. In the present study we aimed at investigating mGFAP-Cre conditional TRPA1 knockout mice in the cuprizone model. These animals were generated by crossbreeding GFAP-Cre+/− and floxed TRPA1 (TRPA1Fl/Fl) mice. Cuprizone was administered for 6 weeks and demyelination was followed by magnetic resonance imaging (MRI). At the end of the treatment, demyelination and glial activation was also investigated by histological methods. The results of the MRI showed that demyelination was milder at weeks 3 and 4 in both homozygous (GFAP-Cre+/− TRPA1Fl/Fl) and heterozygous (GFAP-Cre+/− TRPA1Fl/−) conditional knockout animals compared to Cre−/− control mice. However, by week 6 of the treatment the difference was not detectable by either MRI or histological methods. In conclusion, TRPA1 receptors on astrocytes may transiently contribute to the demyelination induced by cuprizone, however, expression and function of TRPA1 receptors by other cells in the brain (oligodendrocytes, microglia, neurons) warrant further investigation. Full article
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19 pages, 719 KiB  
Review
Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?
by Laura Reiche, Patrick Küry and Peter Göttle
Cells 2019, 8(12), 1591; https://doi.org/10.3390/cells8121591 - 07 Dec 2019
Cited by 18 | Viewed by 4932
Abstract
Down syndrome (DS), or trisomy 21, is the most prevalent chromosomal anomaly accounting for cognitive impairment and intellectual disability (ID). Neuropathological changes of DS brains are characterized by a reduction in the number of neurons and oligodendrocytes, accompanied by hypomyelination and astrogliosis. Recent [...] Read more.
Down syndrome (DS), or trisomy 21, is the most prevalent chromosomal anomaly accounting for cognitive impairment and intellectual disability (ID). Neuropathological changes of DS brains are characterized by a reduction in the number of neurons and oligodendrocytes, accompanied by hypomyelination and astrogliosis. Recent studies mainly focused on neuronal development in DS, but underestimated the role of glial cells as pathogenic players. Aberrant or impaired differentiation within the oligodendroglial lineage and altered white matter functionality are thought to contribute to central nervous system (CNS) malformations. Given that white matter, comprised of oligodendrocytes and their myelin sheaths, is vital for higher brain function, gathering knowledge about pathways and modulators challenging oligodendrogenesis and cell lineages within DS is essential. This review article discusses to what degree DS-related effects on oligodendroglial cells have been described and presents collected evidence regarding induced cell-fate switches, thereby resulting in an enhanced generation of astrocytes. Moreover, alterations in white matter formation observed in mouse and human post-mortem brains are described. Finally, the rationale for a better understanding of pathways and modulators responsible for the glial cell imbalance as a possible source for future therapeutic interventions is given based on current experience on pro-oligodendroglial treatment approaches developed for demyelinating diseases, such as multiple sclerosis. Full article
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23 pages, 4470 KiB  
Article
Conditional Deletion of LRP1 Leads to Progressive Loss of Recombined NG2-Expressing Oligodendrocyte Precursor Cells in a Novel Mouse Model
by Ina Schäfer, Johannes Kaisler, Anja Scheller, Frank Kirchhoff, Aiden Haghikia and Andreas Faissner
Cells 2019, 8(12), 1550; https://doi.org/10.3390/cells8121550 - 30 Nov 2019
Cited by 11 | Viewed by 3992
Abstract
The low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor, mediating endocytosis and activating intracellular signaling cascades. LRP1 is highly expressed in the central nervous system (CNS), especially in oligodendrocyte precursor cells (OPCs). Previous studies have suggested LRP1 as a regulator in [...] Read more.
The low-density lipoprotein receptor-related protein 1 (LRP1) is a transmembrane receptor, mediating endocytosis and activating intracellular signaling cascades. LRP1 is highly expressed in the central nervous system (CNS), especially in oligodendrocyte precursor cells (OPCs). Previous studies have suggested LRP1 as a regulator in early oligodendrocyte development, repair of chemically induced white matter lesions, and cholesterol homeostasis. To circumvent embryonic lethality observed in the case of global LRP1 deletion, we generated a new inducible conditional knockout (KO) mouse model, which enabled an NG2-restricted LRP1 deficiency (NG2-CreERT2ct2/wtxR26eGFPflox/floxxLRP1flox/flox). When characterizing our triple transgenic mouse model, we noticed a substantial and progressive loss of recombined LRP1-deficient cells in the oligodendrocyte lineage. On the other hand, we found comparable distributions and fractions of oligodendroglia within the Corpus callosum of the KO and control animals, indicating a compensation of these deficits. An initial study on experimental autoimmune encephalomyelitis (EAE) was performed in triple transgenic and control mice and the cell biology of oligodendrocytes obtained from the animals was studied in an in vitro myelination assay. Differences could be observed in these assays, which, however, did not achieve statistical significance, presumably because the majority of recombined LRP1-deficient cells has been replaced by non-recombined cells. Thus, the analysis of the role of LRP1 in EAE will require the induction of acute recombination in the context of the disease process. As LRP1 is necessary for the survival of OPCs in vivo, we assume that it will play an important role in myelin repair. Full article
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15 pages, 596 KiB  
Review
Oligodendrocytes as A New Therapeutic Target in Schizophrenia: From Histopathological Findings to Neuron-Oligodendrocyte Interaction
by Florian J. Raabe, Lenka Slapakova, Moritz J. Rossner, Ludovico Cantuti-Castelvetri, Mikael Simons, Peter G. Falkai and Andrea Schmitt
Cells 2019, 8(12), 1496; https://doi.org/10.3390/cells8121496 - 23 Nov 2019
Cited by 48 | Viewed by 5909
Abstract
Imaging and postmortem studies have revealed disturbed oligodendroglia-related processes in patients with schizophrenia and provided much evidence for disturbed myelination, irregular gene expression, and altered numbers of oligodendrocytes in the brains of schizophrenia patients. Oligodendrocyte deficits in schizophrenia might be a result of [...] Read more.
Imaging and postmortem studies have revealed disturbed oligodendroglia-related processes in patients with schizophrenia and provided much evidence for disturbed myelination, irregular gene expression, and altered numbers of oligodendrocytes in the brains of schizophrenia patients. Oligodendrocyte deficits in schizophrenia might be a result of failed maturation and disturbed regeneration and may underlie the cognitive deficits of the disease, which are strongly associated with impaired long-term outcome. Cognition depends on the coordinated activity of neurons and interneurons and intact connectivity. Oligodendrocyte precursors form a synaptic network with parvalbuminergic interneurons, and disturbed crosstalk between these cells may be a cellular basis of pathology in schizophrenia. However, very little is known about the exact axon-glial cellular and molecular processes that may be disturbed in schizophrenia. Until now, investigations were restricted to peripheral tissues, such as blood, correlative imaging studies, genetics, and molecular and histological analyses of postmortem brain samples. The advent of human-induced pluripotent stem cells (hiPSCs) will enable functional analysis in patient-derived living cells and holds great potential for understanding the molecular mechanisms of disturbed oligodendroglial function in schizophrenia. Targeting such mechanisms may contribute to new treatment strategies for previously treatment-resistant cognitive symptoms. Full article
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21 pages, 1252 KiB  
Article
High Speed Ventral Plane Videography as a Convenient Tool to Quantify Motor Deficits during Pre-Clinical Experimental Autoimmune Encephalomyelitis
by Jiangshan Zhan, Vladislav Yakimov, Sebastian Rühling, Felix Fischbach, Elena Nikolova, Sarah Joost, Hannes Kaddatz, Theresa Greiner, Julia Frenz, Carsten Holzmann and Markus Kipp
Cells 2019, 8(11), 1439; https://doi.org/10.3390/cells8111439 - 14 Nov 2019
Cited by 17 | Viewed by 3237
Abstract
Experimental autoimmune encephalomyelitis (EAE) is the most commonly used multiple sclerosis animal model. EAE mice typically develop motor deficits in a caudal-to-rostral pattern when inflammatory lesions have already developed. However, to monitor more subtle behavioral deficits during lesion development (i.e., pre-clinical phase), more [...] Read more.
Experimental autoimmune encephalomyelitis (EAE) is the most commonly used multiple sclerosis animal model. EAE mice typically develop motor deficits in a caudal-to-rostral pattern when inflammatory lesions have already developed. However, to monitor more subtle behavioral deficits during lesion development (i.e., pre-clinical phase), more sophisticated methods are needed. Here, we investigated whether high speed ventral plane videography can be applied to monitor early motor deficits during ‘pre-clinical’ EAE. For this purpose, EAE was induced in C57BL/6 mice and gait abnormalities were quantified using the DigiGait™ apparatus. Gait deficits were related to histopathological changes. 10 out of 10 control (100%), and 14 out of 18 (77.8%) pre-clinical EAE mice could be evaluated using DigiGait™. EAE severity was not influenced by DigiGait™-related mice handlings. Most gait parameters recorded from day 6 post-immunization until the end of the experiment were found to be stable in control mice. During the pre-clinical phase, when conventional EAE scorings failed to detect any functional impairment, EAE mice showed an increased Swing Time, increased %Swing Stride, decreased %Stance Stride, decreased Stance/Swing, and an increased Absolute Paw Angle. In summary, DigiGait™ is more sensitive than conventional scoring approaches to study motor deficits during the EAE pre-clinical phase. Full article
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23 pages, 845 KiB  
Review
Oligodendrocytes in Development, Myelin Generation and Beyond
by Sarah Kuhn, Laura Gritti, Daniel Crooks and Yvonne Dombrowski
Cells 2019, 8(11), 1424; https://doi.org/10.3390/cells8111424 - 12 Nov 2019
Cited by 289 | Viewed by 29401
Abstract
Oligodendrocytes are the myelinating cells of the central nervous system (CNS) that are generated from oligodendrocyte progenitor cells (OPC). OPC are distributed throughout the CNS and represent a pool of migratory and proliferative adult progenitor cells that can differentiate into oligodendrocytes. The central [...] Read more.
Oligodendrocytes are the myelinating cells of the central nervous system (CNS) that are generated from oligodendrocyte progenitor cells (OPC). OPC are distributed throughout the CNS and represent a pool of migratory and proliferative adult progenitor cells that can differentiate into oligodendrocytes. The central function of oligodendrocytes is to generate myelin, which is an extended membrane from the cell that wraps tightly around axons. Due to this energy consuming process and the associated high metabolic turnover oligodendrocytes are vulnerable to cytotoxic and excitotoxic factors. Oligodendrocyte pathology is therefore evident in a range of disorders including multiple sclerosis, schizophrenia and Alzheimer’s disease. Deceased oligodendrocytes can be replenished from the adult OPC pool and lost myelin can be regenerated during remyelination, which can prevent axonal degeneration and can restore function. Cell population studies have recently identified novel immunomodulatory functions of oligodendrocytes, the implications of which, e.g., for diseases with primary oligodendrocyte pathology, are not yet clear. Here, we review the journey of oligodendrocytes from the embryonic stage to their role in homeostasis and their fate in disease. We will also discuss the most common models used to study oligodendrocytes and describe newly discovered functions of oligodendrocytes. Full article
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13 pages, 2845 KiB  
Article
Combinatory Multifactor Treatment Effects on Primary Nanofiber Oligodendrocyte Cultures
by Lukas S. Enz, Thomas Zeis, Annalisa Hauck, Christopher Linington and Nicole Schaeren-Wiemers
Cells 2019, 8(11), 1422; https://doi.org/10.3390/cells8111422 - 12 Nov 2019
Cited by 4 | Viewed by 2824
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system. Neurological deficits are attributed to inflammatory demyelination, which compromises axonal function and survival. These are mitigated in experimental models by rapid and often complete remyelination of affected [...] Read more.
Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system. Neurological deficits are attributed to inflammatory demyelination, which compromises axonal function and survival. These are mitigated in experimental models by rapid and often complete remyelination of affected axons, but in MS this endogenous repair mechanism frequently fails, leaving axons increasingly vulnerable to the detrimental effects of inflammatory and metabolic stress. Understanding the molecular basis of remyelination and remyelination failure is essential to develop improved therapies for this devastating disease. However, recent studies suggest that this is not due to a single dominant mechanism, but rather represents the biological outcome of multiple changes in the lesion microenvironment that combine to disrupt oligodendrocyte differentiation. This identifies a pressing need to develop technical platforms to investigate combinatory and/or synergistic effects of factors differentially expressed in MS lesions on oligodendrocyte proliferation and differentiation. Here we describe protocols using primary oligodendrocyte cultures from Bl6 mice on 384-well nanofiber plates to model changes affecting oligodendrogenesis and differentiation in the complex signaling environment associated with multiple sclerosis lesions. Using platelet-derived growth factor (PDGF–AA), fibroblast growth factor 2 (FGF2), bone morphogenetic protein 2 (BMP2) and bone morphogenetic protein 4 (BMP4) as representative targets, we demonstrate that we can assess their combinatory effects across a wide range of concentrations in a single experiment. This in vitro model is ideal for assessing the combinatory effects of changes in availability of multiple factors, thus more closely modelling the situation in vivo and furthering high-throughput screening possibilities. Full article
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15 pages, 20369 KiB  
Article
Detrimental Impact of Energy Drink Compounds on Developing Oligodendrocytes and Neurons
by Meray Serdar, Annika Mordelt, Katharina Müser, Karina Kempe, Ursula Felderhoff-Müser, Josephine Herz and Ivo Bendix
Cells 2019, 8(11), 1381; https://doi.org/10.3390/cells8111381 - 03 Nov 2019
Cited by 12 | Viewed by 4231
Abstract
The consumption of energy drinks is continuously rising, particularly in children and adolescents. While risks for adverse health effects, like arrhythmia, have been described, effects on neural cells remain elusive. Considering that neurodevelopmental processes like myelination and neuronal network formation peak in childhood [...] Read more.
The consumption of energy drinks is continuously rising, particularly in children and adolescents. While risks for adverse health effects, like arrhythmia, have been described, effects on neural cells remain elusive. Considering that neurodevelopmental processes like myelination and neuronal network formation peak in childhood and adolescence we hypothesized that developing oligodendrocytes and neurons are particularly vulnerable to main energy drink components. Immature oligodendrocytes and hippocampal neurons were isolated from P0-P1 Wistar rats and were incubated with 0.3 mg/mL caffeine and 4 mg/mL taurine alone or in combination for 24 h. Analysis was performed immediately after treatment or after additional three days under differentiating conditions for oligodendrocytes and standard culture for neurons. Oligodendrocyte degeneration, proliferation, and differentiation were assessed via immunocytochemistry and immunoblotting. Neuronal integrity was investigated following immunocytochemistry by analysis of dendrite outgrowth and axonal morphology. Caffeine and taurine induced an increased degeneration and inhibited proliferation of immature oligodendrocytes accompanied by a decreased differentiation capacity. Moreover, dendritic branching and axonal integrity of hippocampal neurons were negatively affected by caffeine and taurine treatment. The negative impact of caffeine and taurine on developing oligodendrocytes and disturbed neuronal morphology indicates a high risk for disturbed neurodevelopment in children and adolescents by excessive energy drink consumption. Full article
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16 pages, 22013 KiB  
Article
Laquinimod Supports Remyelination in Non-Supportive Environments
by Stella Nyamoya, Julia Steinle, Uta Chrzanowski, Joel Kaye, Christoph Schmitz, Cordian Beyer and Markus Kipp
Cells 2019, 8(11), 1363; https://doi.org/10.3390/cells8111363 - 31 Oct 2019
Cited by 13 | Viewed by 3109
Abstract
Inflammatory demyelination, which is a characteristic of multiple sclerosis lesions, leads to acute functional deficits and, in the long term, to progressive axonal degeneration. While remyelination is believed to protect axons, the endogenous-regenerative processes are often incomplete or even completely fail in many [...] Read more.
Inflammatory demyelination, which is a characteristic of multiple sclerosis lesions, leads to acute functional deficits and, in the long term, to progressive axonal degeneration. While remyelination is believed to protect axons, the endogenous-regenerative processes are often incomplete or even completely fail in many multiple sclerosis patients. Although it is currently unknown why remyelination fails, recurrent demyelination of previously demyelinated white matter areas is one contributing factor. In this study, we investigated whether laquinimod, which has demonstrated protective effects in active multiple sclerosis patients, protects against recurrent demyelination. To address this, male mice were intoxicated with cuprizone for up to eight weeks and treated with either a vehicle solution or laquinimod at the beginning of week 5, where remyelination was ongoing. The brains were harvested and analyzed by immunohistochemistry. At the time-point of laquinimod treatment initiation, oligodendrocyte progenitor cells proliferated and maturated despite ongoing demyelination activity. In the following weeks, myelination recovered in the laquinimod- but not vehicle-treated mice, despite continued cuprizone intoxication. Myelin recovery was paralleled by less severe microgliosis and acute axonal injury. In this study, we were able to demonstrate that laquinimod, which has previously been shown to protect against cuprizone-induced oligodendrocyte degeneration, exerts protective effects during oligodendrocyte progenitor differentiation as well. By this mechanism, laquinimod allows remyelination in non-supportive environments. These results should encourage further clinical studies in progressive multiple sclerosis patients. Full article
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19 pages, 694 KiB  
Review
From OPC to Oligodendrocyte: An Epigenetic Journey
by Assia Tiane, Melissa Schepers, Ben Rombaut, Raymond Hupperts, Jos Prickaerts, Niels Hellings, Daniel van den Hove and Tim Vanmierlo
Cells 2019, 8(10), 1236; https://doi.org/10.3390/cells8101236 - 11 Oct 2019
Cited by 66 | Viewed by 9103
Abstract
Oligodendrocytes provide metabolic and functional support to neuronal cells, rendering them key players in the functioning of the central nervous system. Oligodendrocytes need to be newly formed from a pool of oligodendrocyte precursor cells (OPCs). The differentiation of OPCs into mature and myelinating [...] Read more.
Oligodendrocytes provide metabolic and functional support to neuronal cells, rendering them key players in the functioning of the central nervous system. Oligodendrocytes need to be newly formed from a pool of oligodendrocyte precursor cells (OPCs). The differentiation of OPCs into mature and myelinating cells is a multistep process, tightly controlled by spatiotemporal activation and repression of specific growth and transcription factors. While oligodendrocyte turnover is rather slow under physiological conditions, a disruption in this balanced differentiation process, for example in case of a differentiation block, could have devastating consequences during ageing and in pathological conditions, such as multiple sclerosis. Over the recent years, increasing evidence has shown that epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNAs, are major contributors to OPC differentiation. In this review, we discuss how these epigenetic mechanisms orchestrate and influence oligodendrocyte maturation. These insights are a crucial starting point for studies that aim to identify the contribution of epigenetics in demyelinating diseases and may thus provide new therapeutic targets to induce myelin repair in the long run. Full article
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18 pages, 3863 KiB  
Article
Quantitative Imaging of White and Gray Matter Remyelination in the Cuprizone Demyelination Model Using the Macromolecular Proton Fraction
by Marina Khodanovich, Anna Pishchelko, Valentina Glazacheva, Edgar Pan, Andrey Akulov, Mikhail Svetlik, Yana Tyumentseva, Tatyana Anan’ina and Vasily Yarnykh
Cells 2019, 8(10), 1204; https://doi.org/10.3390/cells8101204 - 05 Oct 2019
Cited by 34 | Viewed by 6698
Abstract
Macromolecular proton fraction (MPF) has been established as a quantitative clinically-targeted MRI myelin biomarker based on recent demyelination studies. This study aimed to assess the capability of MPF to quantify remyelination using the murine cuprizone-induced reversible demyelination model. MPF was measured in vivo [...] Read more.
Macromolecular proton fraction (MPF) has been established as a quantitative clinically-targeted MRI myelin biomarker based on recent demyelination studies. This study aimed to assess the capability of MPF to quantify remyelination using the murine cuprizone-induced reversible demyelination model. MPF was measured in vivo using the fast single-point method in three animal groups (control, cuprizone-induced demyelination, and remyelination after cuprizone withdrawal) and compared to quantitative immunohistochemistry for myelin basic protein (MBP), myelinating oligodendrocytes (CNP-positive cells), and oligodendrocyte precursor cells (OPC, NG2-positive cells) in the corpus callosum, caudate putamen, hippocampus, and cortex. In the demyelination group, MPF, MBP-stained area, and oligodendrocyte count were significantly reduced, while OPC count was significantly increased as compared to both control and remyelination groups in all anatomic structures (p < 0.05). All variables were similar in the control and remyelination groups. MPF and MBP-stained area strongly correlated in each anatomic structure (Pearson’s correlation coefficients, r = 0.80–0.90, p < 0.001). MPF and MBP correlated positively with oligodendrocyte count (r = 0.70–0.84, p < 0.01 for MPF; r = 0.81–0.92, p < 0.001 for MBP) and negatively with OPC count (r = −0.69–−0.77, p < 0.01 for MPF; r = −0.72–−0.89, p < 0.01 for MBP). This study provides immunohistological validation of fast MPF mapping as a non-invasive tool for quantitative assessment of de- and remyelination in white and gray matter and indicates the feasibility of using MPF as a surrogate marker of reparative processes in demyelinating diseases. Full article
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17 pages, 2957 KiB  
Article
Stereological Investigation of Regional Brain Volumes after Acute and Chronic Cuprizone-Induced Demyelination
by Tanja Hochstrasser, Sebastian Rühling, Kerstin Hecher, Kai H. Fabisch, Uta Chrzanowski, Matthias Brendel, Florian Eckenweber, Christian Sacher, Christoph Schmitz and Markus Kipp
Cells 2019, 8(9), 1024; https://doi.org/10.3390/cells8091024 - 03 Sep 2019
Cited by 6 | Viewed by 3885
Abstract
Brain volume measurement is one of the most frequently used biomarkers to establish neuroprotective effects during pre-clinical multiple sclerosis (MS) studies. Furthermore, whole-brain atrophy estimates in MS correlate more robustly with clinical disability than traditional, lesion-based metrics. However, the underlying mechanisms leading to [...] Read more.
Brain volume measurement is one of the most frequently used biomarkers to establish neuroprotective effects during pre-clinical multiple sclerosis (MS) studies. Furthermore, whole-brain atrophy estimates in MS correlate more robustly with clinical disability than traditional, lesion-based metrics. However, the underlying mechanisms leading to brain atrophy are poorly understood, partly due to the lack of appropriate animal models to study this aspect of the disease. The purpose of this study was to assess brain volumes and neuro-axonal degeneration after acute and chronic cuprizone-induced demyelination. C57BL/6 male mice were intoxicated with cuprizone for up to 12 weeks. Brain volume, as well as total numbers and densities of neurons, were determined using design-based stereology. After five weeks of cuprizone intoxication, despite severe demyelination, brain volumes were not altered at this time point. After 12 weeks of cuprizone intoxication, a significant volume reduction was found in the corpus callosum and diverse subcortical areas, particularly the internal capsule and the thalamus. Thalamic volume loss was accompanied by glucose hypermetabolism, analyzed by [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography. This study demonstrates region-specific brain atrophy of different subcortical brain regions after chronic cuprizone-induced demyelination. The chronic cuprizone demyelination model in male mice is, thus, a useful tool to study the underlying mechanisms of subcortical brain atrophy and to investigate the effectiveness of therapeutic interventions. Full article
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22 pages, 7752 KiB  
Article
EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP
by Emanuela Nocita, Alice Del Giovane, Marta Tiberi, Laura Boccuni, Denise Fiorelli, Carola Sposato, Elena Romano, Francesco Basoli, Marcella Trombetta, Alberto Rainer, Enrico Traversa and Antonella Ragnini-Wilson
Cells 2019, 8(8), 844; https://doi.org/10.3390/cells8080844 - 06 Aug 2019
Cited by 11 | Viewed by 4784
Abstract
Remyelination in the adult brain relies on the reactivation of the Neuronal Precursor Cell (NPC) niche and differentiation into Oligodendrocyte Precursor Cells (OPCs) as well as on OPC maturation into myelinating oligodendrocytes (OLs). These two distinct phases in OL development are defined by [...] Read more.
Remyelination in the adult brain relies on the reactivation of the Neuronal Precursor Cell (NPC) niche and differentiation into Oligodendrocyte Precursor Cells (OPCs) as well as on OPC maturation into myelinating oligodendrocytes (OLs). These two distinct phases in OL development are defined by transcriptional and morphological changes. How this differentiation program is controlled remains unclear. We used two drugs that stimulate myelin basic protein (MBP) expression (Clobetasol and Gefitinib) alone or combined with epidermal growth factor receptor (EGFR) or Retinoid X Receptor gamma (RXRγ) gene silencing to decode the receptor signaling required for OPC differentiation in myelinating OLs. Electrospun polystyrene (PS) microfibers were used as synthetic axons to study drug efficacy on fiber engagement. We show that EGFR inhibition per se stimulates MBP expression and increases Clobetasol efficacy in OPC differentiation. Consistent with this, Clobetasol and Gefitinib co-treatment, by co-regulating RXRγ, MBP and phosphatidylinositol 4,5-bisphosphate (PIP2) levels, maximizes synthetic axon engagement. Conversely, RXRγ gene silencing reduces the ability of the drugs to promote MBP expression. This work provides a view of how EGFR/ErbB inhibition controls OPC differentiation and indicates the combination of Clobetasol and Gefitinib as a potent remyelination-enhancing treatment. Full article
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16 pages, 5086 KiB  
Article
Agenesis and Hypomyelination of Corpus Callosum in Mice Lacking Nsun5, an RNA Methyltransferase
by Zihao Yuan, Peipei Chen, Tingting Zhang, Bin Shen and Ling Chen
Cells 2019, 8(6), 552; https://doi.org/10.3390/cells8060552 - 06 Jun 2019
Cited by 15 | Viewed by 4569
Abstract
Williams-Beuren syndrome (WBS) is caused by microdeletions of 28 genes and is characterized by cognitive disorder and hypotrophic corpus callosum (CC). Nsun5 gene, which encodes cytosine-5 RNA methyltransferase, is located in the deletion loci of WBS. We have reported that single-gene knockout of [...] Read more.
Williams-Beuren syndrome (WBS) is caused by microdeletions of 28 genes and is characterized by cognitive disorder and hypotrophic corpus callosum (CC). Nsun5 gene, which encodes cytosine-5 RNA methyltransferase, is located in the deletion loci of WBS. We have reported that single-gene knockout of Nsun5 (Nsun5-KO) in mice impairs spatial cognition. Herein, we report that postnatal day (PND) 60 Nsun5-KO mice showed the volumetric reduction of CC with a decline in the number of myelinated axons and loose myelin sheath. Nsun5 was highly expressed in callosal oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs) from PND7 to PND28. The numbers of OPCs and OLs in CC of PND7-28 Nsun5-KO mice were significantly reduced compared to wild-type littermates. Immunohistochemistry and Western blot analyses of myelin basic protein (MBP) showed the hypomyelination in the CC of PND28 Nsun5-KO mice. The Nsun5 deletion suppressed the proliferation of OPCs but did not affect transition of radial glial cells into OPCs or cell cycle exit of OPCs. The protein levels, rather than transcriptional levels, of CDK1, CDK2 and Cdc42 in the CC of PND7 and PND14 Nsun5-KO mice were reduced. These findings point to the involvement of Nsun5 deletion in agenesis of CC observed in WBS. Full article
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14 pages, 1828 KiB  
Article
Membrane Protein Identification in Rodent Brain Tissue Samples and Acute Brain Slices
by Sarah Joost, Stefan Mikkat, Michael Wille, Antje Schümann and Oliver Schmitt
Cells 2019, 8(5), 423; https://doi.org/10.3390/cells8050423 - 08 May 2019
Cited by 2 | Viewed by 3862
Abstract
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 [...] Read more.
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. Full article
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