المؤلفون: Kapell, Hannah, Fazio, Luca, Dyckow, Julia, Schwarz, Sophia, Cruz-Herranz, Andrés, Mayer, Christina, Campos, Joaquin, D´Este, Elisa, Möbius, Wiebke, Cordano, Christian, Pröbstel, Anne-Katrin, Gharagozloo, Marjan, Zulji, Amel, Naik, Venu Narayanan, Delank, Anna-Katharina, Cerina, Manuela, Müntefering, Thomas, Lerma-Martin, Celia, Sonner, Jana K, Sin, Jung H, Disse, Paul, Rychlik, Nicole, Sabeur, Khalida, Chavali, Manideep, Srivastava, Rajneesh, Heidenreich, Matthias, Fitzgerald, Kathryn C, Seebohm, Guiscard, Stadelmann, Christine, Hemmer, Bernhard, Platten, Michael, Jentsch, Thomas J, Engelhardt, Maren, Budde, Thomas, Nave, Klaus-Armin, Calabresi, Peter A, Friese, Manuel A, Green, Ari J, Acuna, Claudio, Rowitch, David H, Meuth, Sven G, Schirmer, Lucas

المصدر: Journal of Clinical Investigation. 133(7)

مصطلحات موضوعية: Neurosciences, Brain Disorders, Multiple Sclerosis, Autoimmune Disease, Neurodegenerative, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Mice, Animals, Humans, Ranvier's Nodes, Potassium, Neurons, Oligodendroglia, Encephalomyelitis, Autoimmune, Experimental, Inflammation, Multiple sclerosis, Neurodegeneration, Neuroscience, Potassium channels, Medical and Health Sciences, Immunology

الوصف: Multiple sclerosis (MS) is a progressive inflammatory demyelinating disease of the CNS. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward-rectifying) and oligodendroglial Kir4.1 (inward-rectifying) potassium channels have important roles in regulating neuronal excitability at and around the nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE), with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs, and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient (OL-Kir4.1-deficient) mice. In summary, our findings indicate that neuron-OL compensatory interactions promoted resilience through Kv7 and Kir4.1 channels and identify pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8ct4x091Test

المؤلفون: Looser, Zoe J., Faik, Zainab, Ravotto, Luca, Zanker, Henri S., Jung, Ramona B., Werner, Hauke B., Ruhwedel, Torben, Möbius, Wiebke, Bergles, Dwight E., Barros, L. Felipe, Saab, Aiman S.

المساهمون: Looser, Zoe J., Faik, Zainab, Ravotto, Luca, Zanker, Henri S., Jung, Ramona B., Werner, Hauke B., Ruhwedel, Torben, Möbius, Wiebke, Bergles, Dwight E., Barros, L. Felipe, Saab, Aiman S.

الوصف: The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs). To determine how OLs detect axonal spiking and how rapid axon–OL metabolic coupling is regulated in the white matter, we studied activity-dependent calcium (Ca 2+ ) and metabolite fluxes in the mouse optic nerve. We show that fast axonal spiking triggers Ca 2+ signaling and glycolysis in OLs. OLs detect axonal activity through increases in extracellular potassium (K + ) concentrations and activation of Kir4.1 channels, thereby regulating metabolite supply to axons. Both pharmacological inhibition and OL-specific inactivation of Kir4.1 reduce the activity-induced axonal lactate surge. Mice lacking oligodendroglial Kir4.1 exhibit lower resting lactate levels and altered glucose metabolism in axons. These early deficits in axonal energy metabolism are associated with late-onset axonopathy. Our findings reveal that OLs detect fast axonal spiking through K + signaling, making acute metabolic coupling possible and adjusting the axon–OL metabolic unit to promote axonal health.

العلاقة: https://resolver.sub.uni-goettingen.de/purl?gro-2/140366Test; 1558

الإتاحة: https://doi.org/10.1038/s41593-023-01558-3Test
https://resolver.sub.uni-goettingen.de/purl?gro-2/140366Test

المؤلفون: van Belle, Gijsbert J., Zieseniss, Anke, Heidenreich, Doris, Olmos, Maxime, Zhuikova, Asia, Möbius, Wiebke, Paul, Maarten W., Katschinski, Dörthe M.

المساهمون: van Belle, Gijsbert J., Zieseniss, Anke, Heidenreich, Doris, Olmos, Maxime, Zhuikova, Asia, Möbius, Wiebke, Paul, Maarten W., Katschinski, Dörthe M.

الوصف: Clathrin-associated trafficking is a major mechanism for intracellular communication, as well as for cells to communicate with the extracellular environment. A decreased oxygen availability termed hypoxia has been described to influence this mechanism in the past. Mostly biochemical studies were applied in these analyses, which miss spatiotemporal information. We have applied live cell microscopy and a newly developed analysis script in combination with a GFP-tagged clathrin-expressing cell line to obtain insight into the dynamics of the effect of hypoxia. Number, mobility and directionality of clathrin-coated vesicles were analysed in non-stimulated cells as well as after stimulation with epidermal growth factor (EGF) or transferrin in normoxic and hypoxic conditions. These data reveal cargo-specific effects, which would not be observable with biochemical methods or with fixed cells and add to the understanding of cell physiology in hypoxia. The stimulus-dependent consequences were also reflected in the final cellular output, i.e. decreased EGF signaling and in contrast increased iron uptake in hypoxia.

العلاقة: https://resolver.sub.uni-goettingen.de/purl?gro-2/140304Test; 2911

الإتاحة: https://doi.org/10.1007/s00424-024-02911-6Test
https://resolver.sub.uni-goettingen.de/purl?gro-2/140304Test

المؤلفون: Hintze, Anika, Lange, Felix, Steyer, Anna M., Anstatt, Jannis, Möbius, Wiebke, Jakobs, Stefan, Wichmann, Carolin

المساهمون: Hintze, Anika, Lange, Felix, Steyer, Anna M., Anstatt, Jannis, Möbius, Wiebke, Jakobs, Stefan, Wichmann, Carolin

العلاقة: EXC 2067: Multiscale Bioimaging; SFB 1286: Quantitative Synaptologie; SFB 1286 %7C A04: Aktivitätsabhängige morphologische Veränderungen am Endkolben von Held-Synapsen; SFB 1286 %7C A05: Mitochondriale Heterogenität in Synapsen; FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala; FOR 2848 %7C P04: Analyse der räumlichen Organisation der OXPHOS Assemblierung in Säugerzellen; FOR 2848 %7C P08: Strukturelle und funktionale Veränderungen der inneren mitochondrialen Membran axonaler Mitochondrien in vivo in einem dymyelinisierenden Mausmodell; https://resolver.sub.uni-goettingen.de/purl?gro-2/139995Test; https://mbexc.uni-goettingen.de/literature/publications/793Test; https://sfb1286.uni-goettingen.de/literature/publications/233Test; https://for2848.gwdguser.de/literature/publications/47Test

الإتاحة: https://doi.org/10.1016/j.isci.2023.108700Test
https://resolver.sub.uni-goettingen.de/purl?gro-2/139995Test
https://mbexc.uni-goettingen.de/literature/publications/793Test
https://sfb1286.uni-goettingen.de/literature/publications/233Test
https://for2848.gwdguser.de/literature/publications/47Test

المؤلفون: Foerster, Sarah, Floriddia, Elisa M, van Bruggen, David, Kukanja, Petra, Hervé, Bastien, Cheng, Shangli, Kim, Eosu, Phillips, Benjamin U, Heath, Christopher J, Tripathi, Richa B, Call, Cody, Bartels, Theresa, Ridley, Katherine, Neumann, Björn, López-Cruz, Laura, Crawford, Abbe H, Lynch, Cian J, Serrano, Manuel, Saksida, Lisa, Rowitch, David H, Möbius, Wiebke, Nave, Klaus-Armin, Rasband, Matthew N, Bergles, Dwight E, Kessaris, Nicoletta, Richardson, William D, Bussey, Timothy J, Zhao, Chao, Castelo-Branco, Gonçalo, Franklin, Robin JM

مصطلحات موضوعية: 5202 Biological Psychology, 32 Biomedical and Clinical Sciences, 3209 Neurosciences, 52 Psychology, Stem Cell Research - Nonembryonic - Non-Human, Neurosciences, Stem Cell Research, Genetics, Brain Disorders, Neurodegenerative, 1 Underpinning research, 1.1 Normal biological development and functioning, Neurological

الوصف: In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system become populated and myelinated by OLCs of ventral origin. These ectopic oligodendrocytes (eOLs) have a distinctive gene expression profile as well as subtle myelination abnormalities. The failure of eOLs to fully assume the role of the original dorsally derived cells results in locomotor and cognitive deficits in the adult animal. This study reveals the importance of developmental heterogeneity within the oligodendrocyte lineage and its importance for homeostatic brain function. ; We thank Dr Daniel Morrison, Matthew Gratian and Mark Bowen for technical support. Funding: This work was supported by the UK Multiple Sclerosis Society (RJMF/CZ), and The Adelson Medical Research Foundation (RJMF/DHR/K-AN/MR/DEB); the Swedish Research Council (grant 2015-03558 and 2019-01360), the European Union (Horizon 2020 Research and Innovation Programme/European Research Council Consolidator Grant EPIScOPE, grant agreement number 681893), the Swedish Brain Foundation (FO2017-0075), Knut and Alice Wallenberg Foundation (grant 2019-0107 and 2019-0089), The Swedish Society for Medical Research (SSMF, grant JUB2019), the G.ran Gustafsson Foundation for Research in Natural Sciences and Medicine, Strategic Research Programme in Neuroscience (StratNeuro), Ming Wai Lau Centre for Reparative Medicine and Karolinska Institutet (GC-B); the Medical Research Council (G0800575) (NK and WDR); a Project Grant from the National Centre for the Replacement, Refinement, & Reduction of Animals in Research (NC/N001451/1) ...

وصف الملف: application/pdf

العلاقة: https://www.repository.cam.ac.uk/handle/1810/369231.2Test

الإتاحة: https://www.repository.cam.ac.uk/handle/1810/369231.2Test

المؤلفون: Späte, Erik, Zhou, Baoyu, Sun, Ting, Kusch, Kathrin, Asadollahi, Ebrahim, Siems, Sophie B., Depp, Constanze, Werner, Hauke B., Saher, Gesine, Hirrlinger, Johannes, Möbius, Wiebke, Nave, Klaus‐Armin, Goebbels, Sandra

المساهمون: European Research Council, Deutsche Forschungsgemeinschaft

المصدر: Glia ; ISSN 0894-1491 1098-1136

الوصف: Oligodendrocytes and astrocytes are metabolically coupled to neuronal compartments. Pyruvate and lactate can shuttle between glial cells and axons via monocarboxylate transporters. However, lactate can only be synthesized or used in metabolic reactions with the help of lactate dehydrogenase (LDH), a tetramer of LDHA and LDHB subunits in varying compositions. Here we show that mice with a cell type‐specific disruption of both Ldha and Ldhb genes in oligodendrocytes lack a pathological phenotype that would be indicative of oligodendroglial dysfunctions or lack of axonal metabolic support. Indeed, when combining immunohistochemical, electron microscopical, and in situ hybridization analyses in adult mice, we found that the vast majority of mature oligodendrocytes lack detectable expression of LDH. Even in neurodegenerative disease models and in mice under metabolic stress LDH was not increased. In contrast, at early development and in the remyelinating brain, LDHA was readily detectable in immature oligodendrocytes. Interestingly, by immunoelectron microscopy LDHA was particularly enriched at gap junctions formed between adjacent astrocytes and at junctions between astrocytes and oligodendrocytes. Our data suggest that oligodendrocytes metabolize lactate during development and remyelination. In contrast, for metabolic support of axons mature oligodendrocytes may export their own glycolysis products as pyruvate rather than lactate. Lacking LDH, these oligodendrocytes can also “funnel” lactate through their “myelinic” channels between gap junction‐coupled astrocytes and axons without metabolizing it. We suggest a working model, in which the unequal cellular distribution of LDH in white matter tracts facilitates a rapid and efficient transport of glycolysis products among glial and axonal compartments.

الإتاحة: https://doi.org/10.1002/glia.24533Test

المؤلفون: Michanski, Susann, Kapoor, Rohan, Steyer, Anna M., Möbius, Wiebke, Früholz, Iris, Ackermann, Frauke, Gültas, Mehmet, Garner, Craig C., Hamra, F. Kent, Neef, Jakob, Wichmann, Carolin

المساهمون: Michanski, Susann, Kapoor, Rohan, Steyer, Anna M., Möbius, Wiebke, Früholz, Iris, Ackermann, Frauke, Gültas, Mehmet, Garner, Craig C., Hamra, F. Kent, Neef, Jakob, Wichmann, Carolin

الوصف: Cochlear inner hair cells (IHCs) form specialized ribbon synapses with spiral ganglion neurons that tirelessly transmit sound information at high rates over long time periods with extreme temporal precision. This functional specialization is essential for sound encoding and is attributed to a distinct molecular machinery with unique players or splice variants compared to conventional neuronal synapses. Among these is the active zone (AZ) scaffold protein piccolo/aczonin, which is represented by its short splice variant piccolino at cochlear and retinal ribbon synapses. While the function of piccolo at synapses of the central nervous system has been intensively investigated, the role of piccolino at IHC synapses remains unclear. In this study, we characterize the structure and function of IHC synapses in piccolo gene‐trap mutant rats ( Pclo gt/gt ). We find a mild hearing deficit with elevated thresholds and reduced amplitudes of auditory brainstem responses. Ca 2+ channel distribution and ribbon morphology are altered in apical IHCs, while their presynaptic function seems to be unchanged. We conclude that piccolino contributes to the AZ organization in IHCs and is essential for normal hearing. ; Synopsis image Piccolino regulates ribbon morphology as well as the arrangement of Ca 2+ channels at cochlear ribbon synapses. Lack of piccolino results in mild hearing impairment. Rats lacking piccolino show elevated thresholds and reduced amplitudes of auditory brainstem responses for middle and high sound frequencies, indicating an impairment in synchronous synaptic transmission of sound information. Disruption of piccolino results in two distinct categories of active zones with different ribbon synapse morphologies in mutant inner hair cells, while tethering of synaptic vesicles is normal. Ca 2+ channel clustering is impaired in piccolino‐deficient hair cells, but Ca 2+ currents and exocytosis are unaffected. ; National Institutes of Health https://doi.org/10.13039/100000002Test ; Studienstiftung des Deutschen ...

العلاقة: EXC 2067: Multiscale Bioimaging; FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala; FOR 2848 %7C P08: Strukturelle und funktionale Veränderungen der inneren mitochondrialen Membran axonaler Mitochondrien in vivo in einem dymyelinisierenden Mausmodell; https://resolver.sub.uni-goettingen.de/purl?gro-2/132114Test; https://mbexc.uni-goettingen.de/literature/publications/735Test; https://for2848.gwdguser.de/literature/publications/45Test

الإتاحة: https://doi.org/10.15252/embr.202256702Test
https://resolver.sub.uni-goettingen.de/purl?gro-2/132114Test
https://mbexc.uni-goettingen.de/literature/publications/735Test
https://for2848.gwdguser.de/literature/publications/45Test

المؤلفون: Gąsiorowski, Ludwik, Dittmann, Isabel Lucia, Brand, Jeremias N., Ruhwedel, Torben, Möbius, Wiebke, Egger, Bernhard, Rink, Jochen C.

المساهمون: Gąsiorowski, Ludwik, Dittmann, Isabel Lucia, Brand, Jeremias N., Ruhwedel, Torben, Möbius, Wiebke, Egger, Bernhard, Rink, Jochen C.

الوصف: Background Unlike most free-living platyhelminths, catenulids, the sister group to all remaining flatworms, do not have eyes. Instead, the most prominent sensory structures in their heads are statocysts or sensory pits. The latter, found in the family Stenostomidae, are concave depressions located laterally on the head that represent one of the taxonomically important traits of the family. In the past, the sensory pits of flatworms have been homologized with the cephalic organs of nemerteans, a clade that occupies a sister position to platyhelminths in some recent phylogenies. To test for this homology, we studied morphology and gene expression in the sensory pits of the catenulid Stenostomum brevipharyngium . Results We used confocal and electron microscopy to investigate the detailed morphology of the sensory pits, as well as their formation during regeneration and asexual reproduction. The most prevalent cell type within the organ is epidermally-derived neuron-like cells that have cell bodies embedded deeply in the brain lobes and long neurite-like processes extending to the bottom of the pit. Those elongated processes are adorned with extensive microvillar projections that fill up the cavity of the pit, but cilia are not associated with the sensory pit. We also studied the expression patterns of some of the transcription factors expressed in the nemertean cephalic organs during the development of the pits . Only a single gene, pax4/6 , is expressed in both the cerebral organs of nemerteans and sensory pits of S. brevipharyngium , challenging the idea of their deep homology. Conclusions Since there is no morphological or molecular correspondence between the sensory pits of Stenostomum and the cerebral organs of nemerteans, we reject their homology. Interestingly, the major cell type contributing to the sensory pits of stenostomids shows ultrastructural similarities to the rhabdomeric photoreceptors of other flatworms and expresses ortholog of the gene pax4/6 , the pan-bilaterian master regulator of ...

العلاقة: https://resolver.sub.uni-goettingen.de/purl?gro-2/139215Test; 1768

الإتاحة: https://doi.org/10.1186/s12915-023-01768-yTest
https://resolver.sub.uni-goettingen.de/purl?gro-2/139215Test

المؤلفون: Reichmann, Jakob, Ruhwedel, Torben, Möbius, Wiebke, Salditt, Tim

المساهمون: Reichmann, Jakob, Ruhwedel, Torben, Möbius, Wiebke, Salditt, Tim

العلاقة: SFB 1456 %7C Cluster A %7C A03: Dimensionality reduction and regression in Wasserstein space for quantitative 3D histology; SFB 1456: Mathematik des Experiments: Die Herausforderung indirekter Messungen in den Naturwissenschaften; https://resolver.sub.uni-goettingen.de/purl?gro-2/118460Test

الإتاحة: https://doi.org/10.1117/1.JMI.10.5.056001Test
https://resolver.sub.uni-goettingen.de/purl?gro-2/118460Test

المؤلفون: Schirmer, Lucas, Möbius, Wiebke, Zhao, Chao, Cruz-Herranz, Andrés, Ben Haim, Lucile, Cordano, Christian, Shiow, Lawrence R, Kelley, Kevin W, Sadowski, Boguslawa, Timmons, Garrett, Pröbstel, Anne-Katrin, Wright, Jackie N, Sin, Jung Hyung, Devereux, Michael, Morrison, Daniel E, Chang, Sandra M, Sabeur, Khalida, Green, Ari J, Nave, Klaus-Armin, Franklin, Robin Jm, Rowitch, David H

مصطلحات موضوعية: Spinal Cord, Neuroglia, Oligodendroglia, Neurons, Axons, Animals, Mice, Knockout, Humans, Mice, Seizures, Potassium Channels, Inwardly Rectifying, Leukoencephalopathies, Kir4.1, mouse, neurobiology, neurodegeneration, neuroscience, oligodendrocytes, visual System, white matter, Knockout, Potassium Channels, Inwardly Rectifying, Biochemistry and Cell Biology

الوصف: Glial support is critical for normal axon function and can become dysregulated in white matter (WM) disease. In humans, loss-of-function mutations of KCNJ10, which encodes the inward-rectifying potassium channel KIR4.1, causes seizures and progressive neurological decline. We investigated Kir4.1 functions in oligodendrocytes (OLs) during development, adulthood and after WM injury. We observed that Kir4.1 channels localized to perinodal areas and the inner myelin tongue, suggesting roles in juxta-axonal K+ removal. Conditional knockout (cKO) of OL-Kcnj10 resulted in late onset mitochondrial damage and axonal degeneration. This was accompanied by neuronal loss and neuro-axonal dysfunction in adult OL-Kcnj10 cKO mice as shown by delayed visual evoked potentials, inner retinal thinning and progressive motor deficits. Axon pathologies in OL-Kcnj10 cKO were exacerbated after WM injury in the spinal cord. Our findings point towards a critical role of OL-Kir4.1 for long-term maintenance of axonal function and integrity during adulthood and after WM injury.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/9g69b3jvTest