Misgeld, Thomas

[["dc.bibliographiccitation.artnumber","e2200302"],["dc.bibliographiccitation.issue","18"],["dc.bibliographiccitation.journal","Small"],["dc.bibliographiccitation.volume","18"],["dc.contributor.author","Khalin, Igor"],["dc.contributor.author","Adarsh, Nagappanpillai"],["dc.contributor.author","Schifferer, Martina"],["dc.contributor.author","Wehn, Antonia"],["dc.contributor.author","Groschup, Bernhard"],["dc.contributor.author","Misgeld, Thomas"],["dc.contributor.author","Klymchenko, Andrey"],["dc.contributor.author","Plesnila, Nikolaus"],["dc.date.accessioned","2022-08-19T08:02:00Z"],["dc.date.available","2022-08-19T08:02:00Z"],["dc.date.issued","2022"],["dc.description.abstract","The current lack of understanding about how nanocarriers cross the blood-brain barrier (BBB) in the healthy and injured brain is hindering the clinical translation of nanoscale brain-targeted drug-delivery systems. Here, the bio-distribution of lipid nano-emulsion droplets (LNDs) of two sizes (30 and 80 nm) in the mouse brain after traumatic brain injury (TBI) is investigated. The highly fluorescent LNDs are prepared by loading them with octadecyl rhodamine B and a bulky hydrophobic counter-ion, tetraphenylborate. Using in vivo two-photon and confocal imaging, the circulation kinetics and bio-distribution of LNDs in the healthy and injured mouse brain are studied. It is found that after TBI, LNDs of both sizes accumulate at vascular occlusions, where specifically 30 nm LNDs extravasate into the brain parenchyma and reach neurons. The vascular occlusions are not associated with bleedings, but instead are surrounded by processes of activated microglia, suggesting a specific opening of the BBB. Finally, correlative light-electron microscopy reveals 30 nm LNDs in endothelial vesicles, while 80 nm particles remain in the vessel lumen, indicating size-selective vesicular transport across the BBB via vascular occlusions. The data suggest that microvascular occlusions serve as \"gates\" for the transport of nanocarriers across the BBB."],["dc.identifier.doi","10.1002/smll.202200302"],["dc.identifier.pmid","35384294"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/113025"],["dc.identifier.url","https://rdp.sfb274.de/literature/publications/63"],["dc.language.iso","en"],["dc.relation","TRR 274: Checkpoints of Central Nervous System Recovery"],["dc.relation","TRR 274 | Z01: Bioimaging Platform"],["dc.relation.eissn","1613-6829"],["dc.relation.issn","1613-6810"],["dc.relation.workinggroup","RG Misgeld"],["dc.relation.workinggroup","RG Schifferer"],["dc.title","Size-Selective Transfer of Lipid Nanoparticle-Based Drug Carriers Across the Blood Brain Barrier Via Vascular Occlusions Following Traumatic Brain Injury"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Neurotherapeutics"],["dc.contributor.author","Kalluri, Sudhakar Reddy"],["dc.contributor.author","Srivastava, Rajneesh"],["dc.contributor.author","Kenet, Selin"],["dc.contributor.author","Tanti, Goutam K."],["dc.contributor.author","Dornmair, Klaus"],["dc.contributor.author","Bennett, Jeffrey L."],["dc.contributor.author","Misgeld, Thomas"],["dc.contributor.author","Hemmer, Bernhard"],["dc.contributor.author","Wyss, Matthias T."],["dc.contributor.author","Herwerth, Marina"],["dc.date.accessioned","2022-08-26T07:55:50Z"],["dc.date.available","2022-08-26T07:55:50Z"],["dc.date.issued","2022-07-12"],["dc.description.abstract","Purinergic 2 receptors (P2Rs) contribute to disease-related immune cell signaling and are upregulated in various pathological settings, including neuroinflammation. P2R inhibitors have been used to treat inflammatory diseases and can protect against complement-mediated cell injury. However, the mechanisms behind these anti-inflammatory properties of P2R inhibitors are not well understood, and their potential in CNS autoimmunity is underexplored. Here, we tested the effects of P2R inhibitors on glial toxicity in a mouse model of neuromyelitis optica spectrum disorder (NMOSD). NMOSD is a destructive CNS autoimmune disorder, in which autoantibodies against astrocytic surface antigen Aquaporin 4 (AQP4) mediate complement-dependent loss of astrocytes. Using two-photon microscopy in vivo, we found that various classes of P2R inhibitors prevented AQP4-IgG/complement-dependent astrocyte death. In vitro, these drugs inhibited the binding of AQP4-IgG or MOG-IgG to their antigen in a dose-dependent manner. Size-exclusion chromatography and circular dichroism spectroscopy revealed a partial unfolding of antibodies in the presence of various P2R inhibitors, suggesting a shared interference with IgG antibodies leading to their conformational change. Our study demonstrates that P2R inhibitors can disrupt complement activation by direct interaction with IgG. This mechanism is likely to influence the role of P2R inhibitors in autoimmune disease models and their therapeutic impact in human disease."],["dc.identifier.doi","10.1007/s13311-022-01269-w"],["dc.identifier.pmid","35821382"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/113251"],["dc.identifier.url","https://rdp.sfb274.de/literature/publications/72"],["dc.language.iso","en"],["dc.relation","TRR 274: Checkpoints of Central Nervous System Recovery"],["dc.relation","TRR 274 | B03: Checkpoints of recovery after primary astrocytic lesions in neuromyelitis optica and related animal models"],["dc.relation.eissn","1878-7479"],["dc.relation.issn","1933-7213"],["dc.relation.workinggroup","RG Misgeld"],["dc.title","P2R Inhibitors Prevent Antibody-Mediated Complement Activation in an Animal Model of Neuromyelitis Optica : P2R Inhibitors Prevent Autoantibody Injury"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4870.e5"],["dc.bibliographiccitation.issue","21"],["dc.bibliographiccitation.journal","Current Biology"],["dc.bibliographiccitation.lastpage","4878.e5"],["dc.bibliographiccitation.volume","31"],["dc.contributor.author","Engerer, Peter"],["dc.contributor.author","Petridou, Eleni"],["dc.contributor.author","Williams, Philip R."],["dc.contributor.author","Suzuki, Sachihiro C."],["dc.contributor.author","Yoshimatsu, Takeshi"],["dc.contributor.author","Portugues, Ruben"],["dc.contributor.author","Misgeld, Thomas"],["dc.contributor.author","Godinho, Leanne"],["dc.date.accessioned","2022-08-19T07:08:06Z"],["dc.date.available","2022-08-19T07:08:06Z"],["dc.date.issued","2021"],["dc.description.abstract","Neuronal identity has long been thought of as immutable, so that once a cell acquires a specific fate, it is maintained for life.1 Studies using the overexpression of potent transcription factors to experimentally reprogram neuronal fate in the mouse neocortex2,3 and retina4,5 have challenged this notion by revealing that post-mitotic neurons can switch their identity. Whether fate reprogramming is part of normal development in the central nervous system (CNS) is unclear. While there are some reports of physiological cell fate reprogramming in invertebrates,6,7 and in the vertebrate peripheral nervous system,8 endogenous fate reprogramming in the vertebrate CNS has not been documented. Here, we demonstrate spontaneous fate re-specification in an interneuron lineage in the zebrafish retina. We show that the visual system homeobox 1 (vsx1)-expressing lineage, which has been associated exclusively with excitatory bipolar cell (BC) interneurons,9-12 also generates inhibitory amacrine cells (ACs). We identify a role for Notch signaling in conferring plasticity to nascent vsx1 BCs, allowing suitable transcription factor programs to re-specify them to an AC fate. Overstimulating Notch signaling enhances this physiological phenotype so that both daughters of a vsx1 progenitor differentiate into ACs and partially differentiated vsx1 BCs can be converted into ACs. Furthermore, this physiological re-specification can be mimicked to allow experimental induction of an entirely distinct fate, that of retinal projection neurons, from the vsx1 lineage. Our observations reveal unanticipated plasticity of cell fate during retinal development."],["dc.identifier.doi","10.1016/j.cub.2021.08.049"],["dc.identifier.pmid","34534440"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/113017"],["dc.identifier.url","https://rdp.sfb274.de/literature/publications/42"],["dc.language.iso","en"],["dc.relation","TRR 274: Checkpoints of Central Nervous System Recovery"],["dc.relation","TRR 274 | C04: Checkpoints of visual circuit repair after acute retinal cell injury"],["dc.relation.eissn","1879-0445"],["dc.relation.issn","0960-9822"],["dc.relation.workinggroup","RG Misgeld"],["dc.relation.workinggroup","RG Portugues (Sensorimotor Control)"],["dc.title","Notch-mediated re-specification of neuronal identity during central nervous system development"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","The Journal of Cell Biology"],["dc.bibliographiccitation.volume","220"],["dc.contributor.author","Wang, Mengzhe"],["dc.contributor.author","Kleele, Tatjana"],["dc.contributor.author","Xiao, Yan"],["dc.contributor.author","Plucinska, Gabriela"],["dc.contributor.author","Avramopoulos, Petros"],["dc.contributor.author","Engelhardt, Stefan"],["dc.contributor.author","Schwab, Markus H."],["dc.contributor.author","Kneussel, Matthias"],["dc.contributor.author","Czopka, Tim"],["dc.contributor.author","Sherman, Diane L."],["dc.contributor.author","Brophy, Peter J."],["dc.contributor.author","Misgeld, Thomas"],["dc.contributor.author","Brill, Monika S."],["dc.date.accessioned","2022-08-18T13:55:47Z"],["dc.date.available","2022-08-18T13:55:47Z"],["dc.date.issued","2021"],["dc.description.abstract","Neuronal remodeling and myelination are two fundamental processes during neurodevelopment. How they influence each other remains largely unknown, even though their coordinated execution is critical for circuit function and often disrupted in neuropsychiatric disorders. It is unclear whether myelination stabilizes axon branches during remodeling or whether ongoing remodeling delays myelination. By modulating synaptic transmission, cytoskeletal dynamics, and axonal transport in mouse motor axons, we show that local axon remodeling delays myelination onset and node formation. Conversely, glial differentiation does not determine the outcome of axon remodeling. Delayed myelination is not due to a limited supply of structural components of the axon-glial unit but rather is triggered by increased transport of signaling factors that initiate myelination, such as neuregulin. Further, transport of promyelinating signals is regulated via local cytoskeletal maturation related to activity-dependent competition. Our study reveals an axon branch-specific fine-tuning mechanism that locally coordinates axon remodeling and myelination."],["dc.identifier.doi","10.1083/jcb.201911114"],["dc.identifier.pmid","33538762"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/113005"],["dc.identifier.url","https://rdp.sfb274.de/literature/publications/13"],["dc.language.iso","en"],["dc.relation","TRR 274: Checkpoints of Central Nervous System Recovery"],["dc.relation","TRR 274 | B03: Checkpoints of recovery after primary astrocytic lesions in neuromyelitis optica and related animal models"],["dc.relation","TRR 274 | C02: In vivo detection and targeting of calcium clearance and axonal membrane repair after acute CNS insults"],["dc.relation.eissn","1540-8140"],["dc.relation.issn","0021-9525"],["dc.relation.workinggroup","RG Misgeld"],["dc.title","Completion of neuronal remodeling prompts myelination along developing motor axon branches"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","355"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Nature Neuroscience"],["dc.bibliographiccitation.lastpage","367"],["dc.bibliographiccitation.volume","24"],["dc.contributor.author","Jafari, Mehrnoosh"],["dc.contributor.author","Schumacher, Adrian-Minh"],["dc.contributor.author","Snaidero, Nicolas"],["dc.contributor.author","Ullrich Gavilanes, Emily M."],["dc.contributor.author","Neziraj, Tradite"],["dc.contributor.author","Kocsis-Jutka, Virág"],["dc.contributor.author","Engels, Daniel"],["dc.contributor.author","Jürgens, Tanja"],["dc.contributor.author","Wagner, Ingrid"],["dc.contributor.author","Weidinger, Juan Daniel Flórez"],["dc.contributor.author","Schmidt, Stephanie S."],["dc.contributor.author","Beltrán, Eduardo"],["dc.contributor.author","Hagan, Nellwyn"],["dc.contributor.author","Woodworth, Lisa"],["dc.contributor.author","Ofengeim, Dimitry"],["dc.contributor.author","Gans, Joseph"],["dc.contributor.author","Wolf, Fred"],["dc.contributor.author","Kreutzfeldt, Mario"],["dc.contributor.author","Portugues, Ruben"],["dc.contributor.author","Merkler, Doron"],["dc.contributor.author","Misgeld, Thomas"],["dc.contributor.author","Kerschensteiner, Martin"],["dc.date.accessioned","2021-04-14T08:30:17Z"],["dc.date.available","2021-04-14T08:30:17Z"],["dc.date.issued","2021"],["dc.identifier.doi","10.1038/s41593-020-00780-7"],["dc.identifier.pmid","33495636"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83177"],["dc.identifier.url","https://rdp.sfb274.de/literature/publications/12"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/103"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","TRR 274: Checkpoints of Central Nervous System Recovery"],["dc.relation","TRR 274 | B03: Checkpoints of recovery after primary astrocytic lesions in neuromyelitis optica and related animal models"],["dc.relation","TRR 274 | C02: In vivo detection and targeting of calcium clearance and axonal membrane repair after acute CNS insults"],["dc.relation","TRR 274 | C05: Checkpoints for circuit integration of nascent neurons in the injured brain"],["dc.relation","TRR 274 | Z01: Bioimaging Platform"],["dc.relation","TRR 274 | Z02: Genomics and Bioinformatics Platform"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | C02: Aktive Zonendesigns und -dynamiken, die auf das synaptische Arbeitsgedächtnis zugeschnitten sind"],["dc.relation.eissn","1546-1726"],["dc.relation.issn","1097-6256"],["dc.relation.workinggroup","RG Kerschensteiner (Neuroimmune Interactions)"],["dc.relation.workinggroup","RG Misgeld"],["dc.relation.workinggroup","RG Portugues (Sensorimotor Control)"],["dc.relation.workinggroup","RG Wolf"],["dc.title","Phagocyte-mediated synapse removal in cortical neuroinflammation is promoted by local calcium accumulation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","4901"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Snaidero, Nicolas"],["dc.contributor.author","Schifferer, Martina"],["dc.contributor.author","Mezydlo, Aleksandra"],["dc.contributor.author","Zalc, Bernard"],["dc.contributor.author","Kerschensteiner, Martin"],["dc.contributor.author","Misgeld, Thomas"],["dc.date.accessioned","2022-08-18T13:29:08Z"],["dc.date.available","2022-08-18T13:29:08Z"],["dc.date.issued","2020"],["dc.description.abstract","Myelin, rather than being a static insulator of axons, is emerging as an active participant in circuit plasticity. This requires precise regulation of oligodendrocyte numbers and myelination patterns. Here, by devising a laser ablation approach of single oligodendrocytes, followed by in vivo imaging and correlated ultrastructural reconstructions, we report that in mouse cortex demyelination as subtle as the loss of a single oligodendrocyte can trigger robust cell replacement and remyelination timed by myelin breakdown. This results in reliable reestablishment of the original myelin pattern along continuously myelinated axons, while in parallel, patchy isolated internodes emerge on previously unmyelinated axons. Therefore, in mammalian cortex, internodes along partially myelinated cortical axons are typically not reestablished, suggesting that the cues that guide patchy myelination are not preserved through cycles of de- and remyelination. In contrast, myelin sheaths forming continuous patterns show remarkable homeostatic resilience and remyelinate with single axon precision."],["dc.identifier.doi","10.1038/s41467-020-18632-0"],["dc.identifier.pmid","32994410"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/113004"],["dc.identifier.url","https://rdp.sfb274.de/literature/publications/7"],["dc.language.iso","en"],["dc.relation","TRR 274: Checkpoints of Central Nervous System Recovery"],["dc.relation","TRR 274 | B02: Inflammatory neurodegeneration and repair mechanisms in childhood onset autoimmune and neurometabolic demyelinating CNS disease"],["dc.relation","TRR 274 | C02: In vivo detection and targeting of calcium clearance and axonal membrane repair after acute CNS insults"],["dc.relation","TRR 274 | C05: Checkpoints for circuit integration of nascent neurons in the injured brain"],["dc.relation","TRR 274 | Z01: Bioimaging Platform"],["dc.relation.issn","2041-1723"],["dc.relation.workinggroup","RG Kerschensteiner (Neuroimmune Interactions)"],["dc.relation.workinggroup","RG Misgeld"],["dc.relation.workinggroup","RG Schifferer"],["dc.title","Myelin replacement triggered by single-cell demyelination in mouse cortex"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","100232"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","STAR Protocols"],["dc.bibliographiccitation.volume","1"],["dc.contributor.author","Kislinger, Georg"],["dc.contributor.author","Gnägi, Helmut"],["dc.contributor.author","Kerschensteiner, Martin"],["dc.contributor.author","Simons, Mikael"],["dc.contributor.author","Misgeld, Thomas"],["dc.contributor.author","Schifferer, Martina"],["dc.date.accessioned","2022-08-19T06:32:51Z"],["dc.date.available","2022-08-19T06:32:51Z"],["dc.date.issued","2020"],["dc.description.abstract","Here, we describe a detailed workflow for ATUM-FIB microscopy, a hybrid method that combines serial-sectioning scanning electron microscopy (SEM) with focused ion beam SEM (FIB-SEM). This detailed protocol is optimized for mouse cortex samples. The main processing steps include the generation of semi-thick sections from sequentially cured resin blocks using a heated microtomy approach. We demonstrate the different imaging modalities, including serial light and electron microscopy for target recognition and FIB-SEM for isotropic imaging of regions of interest. For complete details on the use and execution of this protocol, please refer to Kislinger et al. (2020)."],["dc.identifier.doi","10.1016/j.xpro.2020.100232"],["dc.identifier.pmid","33377119"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/113013"],["dc.identifier.url","https://rdp.sfb274.de/literature/publications/33"],["dc.language.iso","en"],["dc.relation","TRR 274: Checkpoints of Central Nervous System Recovery"],["dc.relation","TRR 274 | B03: Checkpoints of recovery after primary astrocytic lesions in neuromyelitis optica and related animal models"],["dc.relation","TRR 274 | C02: In vivo detection and targeting of calcium clearance and axonal membrane repair after acute CNS insults"],["dc.relation","TRR 274 | Z01: Bioimaging Platform"],["dc.relation.eissn","2666-1667"],["dc.relation.workinggroup","RG Kerschensteiner (Neuroimmune Interactions)"],["dc.relation.workinggroup","RG Misgeld"],["dc.relation.workinggroup","RG Schifferer"],["dc.relation.workinggroup","RG Simons (The Biology of Glia in Development and Disease)"],["dc.title","ATUM-FIB microscopy for targeting and multiscale imaging of rare events in mouse cortex"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","101290"],["dc.bibliographiccitation.issue","7"],["dc.bibliographiccitation.journal","iScience"],["dc.bibliographiccitation.volume","23"],["dc.contributor.author","Kislinger, Georg"],["dc.contributor.author","Gnägi, Helmut"],["dc.contributor.author","Kerschensteiner, Martin"],["dc.contributor.author","Simons, Mikael"],["dc.contributor.author","Misgeld, Thomas"],["dc.contributor.author","Schifferer, Martina"],["dc.date.accessioned","2022-08-18T13:58:23Z"],["dc.date.available","2022-08-18T13:58:23Z"],["dc.date.issued","2020-07-24"],["dc.description.abstract","Volume electron microscopy enables the ultrastructural analysis of biological tissue. Currently, the techniques involving ultramicrotomy (ATUM, ssTEM) allow large fields of view but afford only limited z-resolution, whereas ion beam-milling approaches (FIB-SEM) yield isotropic voxels but are restricted in volume size. Now we present a hybrid method, named ATUM-FIB, which combines the advantages of both approaches. ATUM-FIB is based on serial sectioning of tissue into \"semithick\" (2-10 μm) sections collected onto tape. Serial light and electron microscopy allows the identification of regions of interest that are then directly accessible for targeted FIB-SEM. The set of semithick sections thus represents a tissue \"library\" which provides three-dimensional context information that can be probed \"on demand\" by local high-resolution analysis. We demonstrate the potential of this technique to reveal the ultrastructure of rare but pathologically important events by identifying microglia contact sites with amyloid plaques in a mouse model of familial Alzheimer's disease."],["dc.identifier.doi","10.1016/j.isci.2020.101290"],["dc.identifier.pmid","32622266"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/113006"],["dc.identifier.url","https://rdp.sfb274.de/literature/publications/15"],["dc.language.iso","en"],["dc.relation","TRR 274: Checkpoints of Central Nervous System Recovery"],["dc.relation","TRR 274 | B03: Checkpoints of recovery after primary astrocytic lesions in neuromyelitis optica and related animal models"],["dc.relation","TRR 274 | C02: In vivo detection and targeting of calcium clearance and axonal membrane repair after acute CNS insults"],["dc.relation","TRR 274 | Z01: Bioimaging Platform"],["dc.relation.eissn","2589-0042"],["dc.relation.workinggroup","RG Kerschensteiner (Neuroimmune Interactions)"],["dc.relation.workinggroup","RG Misgeld"],["dc.relation.workinggroup","RG Schifferer"],["dc.relation.workinggroup","RG Simons (The Biology of Glia in Development and Disease)"],["dc.title","Multiscale ATUM-FIB Microscopy Enables Targeted Ultrastructural Analysis at Isotropic Resolution"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Brain"],["dc.contributor.author","Herwerth, Marina"],["dc.contributor.author","Kenet, Selin"],["dc.contributor.author","Schifferer, Martina"],["dc.contributor.author","Winkler, Anne"],["dc.contributor.author","Weber, Melanie"],["dc.contributor.author","Snaidero, Nicolas"],["dc.contributor.author","Wang, Mengzhe"],["dc.contributor.author","Lohrberg, Melanie"],["dc.contributor.author","Bennett, Jeffrey L."],["dc.contributor.author","Stadelmann, Christine"],["dc.contributor.author","Misgeld, Thomas"],["dc.date.accessioned","2022-04-01T10:02:49Z"],["dc.date.available","2022-04-01T10:02:49Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract Neuromyelitis optica (NMO) is a chronic neuroinflammatory disease, which primarily targets astrocytes and often results in severe axon injury of unknown mechanism. NMO patients harbor autoantibodies against the astrocytic water channel protein, aquaporin-4 (AQP4-IgG), which induce complement-mediated astrocyte lysis and subsequent axon damage. Using spinal in vivo imaging in a mouse model of such astrocytopathic lesions, we explored the mechanism underlying NMO-related axon injury. Many axons showed a swift and morphologically distinct ‘pearls-on-string’ transformation also readily detectable in human NMO lesions, which especially affected small caliber axons independently of myelination. Functional imaging revealed that calcium homeostasis was initially preserved in this ‘acute axonal beading’ state, ruling out disruption of the axonal membrane, which sets this form of axon injury apart from previously described forms of traumatic and inflammatory axon damage. Morphological, pharmacological and genetic analyses showed that AQP4-IgG-induced axon injury involved osmotic stress and ionic overload, but does not appear to use canonical pathways of Wallerian-like degeneration. Subcellular analysis of beaded axons demonstrated remodeling of the axonal cytoskeleton in beaded axons, especially local loss of microtubules. Treatment with the microtubule stabilizer epothilone, a therapy in development for traumatic and degenerative axonopathies, prevented axonal beading, while destabilizing microtubules sensitized axons for beading. Our results reveal a distinct form of immune-mediated axon pathology in NMO that mechanistically differs from known cascades of posttraumatic and inflammatory axon loss, and suggest a new strategy for neuroprotection in NMO and related diseases."],["dc.identifier.doi","10.1093/brain/awac079"],["dc.identifier.pmid","35202467"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/106013"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/454"],["dc.identifier.url","https://rdp.sfb274.de/literature/publications/59"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-530"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","TRR 274: Checkpoints of Central Nervous System Recovery"],["dc.relation.eissn","1460-2156"],["dc.relation.issn","0006-8950"],["dc.relation.workinggroup","RG Stadelmann-Nessler"],["dc.relation.workinggroup","RG Misgeld"],["dc.relation.workinggroup","RG Schifferer"],["dc.rights","CC BY-NC 4.0"],["dc.title","A new form of axonal pathology in a spinal model of neuromyelitis optica"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]