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9 Publications visible to you, out of a total of 9
Microglia-mediated demyelination protects against CD8(+) T cell-driven axon degeneration in mice carrying PLP defects.

Abstract (Expand)

Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic … neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8(+) T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.

Authors: J. Groh, T. Abdelwahab, Y. Kattimani, M. Horner, S. Loserth, V. Gudi, R. Adalbert, F. Imdahl, A. E. Saliba, M. Coleman, M. Stangel, M. Simons, R. Martini

Date Published: 30th Oct 2023

Publication Type: Journal

Spatial Transcriptomics-correlated Electron Microscopy maps transcriptional and ultrastructural responses to brain injury.

Abstract (Expand)

Understanding the complexity of cellular function within a tissue necessitates the combination of multiple phenotypic readouts. Here, we developed a method that links spatially-resolved gene expression … of single cells with their ultrastructural morphology by integrating multiplexed error-robust fluorescence in situ hybridization (MERFISH) and large area volume electron microscopy (EM) on adjacent tissue sections. Using this method, we characterized in situ ultrastructural and transcriptional responses of glial cells and infiltrating T-cells after demyelinating brain injury in male mice. We identified a population of lipid-loaded "foamy" microglia located in the center of remyelinating lesion, as well as rare interferon-responsive microglia, oligodendrocytes, and astrocytes that co-localized with T-cells. We validated our findings using immunocytochemistry and lipid staining-coupled single-cell RNA sequencing. Finally, by integrating these datasets, we detected correlations between full-transcriptome gene expression and ultrastructural features of microglia. Our results offer an integrative view of the spatial, ultrastructural, and transcriptional reorganization of single cells after demyelinating brain injury.

Authors: P. Androvic, M. Schifferer, K. Perez Anderson, L. Cantuti-Castelvetri, H. Jiang, H. Ji, L. Liu, G. Gouna, S. A. Berghoff, S. Besson-Girard, J. Knoferle, M. Simons, O. Gokce

Date Published: 11th Jul 2023

Publication Type: Journal

CD8(+) T cells induce interferon-responsive oligodendrocytes and microglia in white matter aging.

Abstract (Expand)

A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found age-related … alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8(+) T cells in aging white matter. Absence of functional lymphocytes decreased the number of IFN-responsive oligodendrocytes and rescued oligodendrocyte loss, whereas T-cell checkpoint inhibition worsened the aging response. In addition, we identified a subpopulation of lymphocyte-dependent, IFN-responsive microglia in the vicinity of the CD8(+) T cells in aging white matter. In summary, we provide evidence that CD8(+) T-cell-induced, IFN-responsive oligodendrocytes and microglia are important modifiers of white matter aging.

Authors: T. Kaya, N. Mattugini, L. Liu, H. Ji, L. Cantuti-Castelvetri, J. Wu, M. Schifferer, J. Groh, R. Martini, S. Besson-Girard, S. Kaji, A. Liesz, O. Gokce, M. Simons

Date Published: 26th Oct 2022

Publication Type: Journal

Proteomic and lipidomic profiling of demyelinating lesions identifies fatty acids as modulators in lesion recovery.

Abstract (Expand)

After demyelinating injury of the central nervous system, resolution of the mounting acute inflammation is crucial for the initiation of a regenerative response. Here, we aim to identify fatty acids … and lipid mediators that govern the balance of inflammatory reactions within demyelinating lesions. Using lipidomics, we identify bioactive lipids in the resolution phase of inflammation with markedly elevated levels of n-3 polyunsaturated fatty acids. Using fat-1 transgenic mice, which convert n-6 fatty acids to n-3 fatty acids, we find that reduction of the n-6/n-3 ratio decreases the phagocytic infiltrate. In addition, we observe accelerated decline of microglia/macrophages and enhanced generation of oligodendrocytes in aged mice when n-3 fatty acids are shuttled to the brain. Thus, n-3 fatty acids enhance lesion recovery and may, therefore, provide the basis for pro-regenerative medicines of demyelinating diseases in the central nervous system.

Authors: H. Penkert, A. Bertrand, V. Tiwari, S. Breimann, S. A. Muller, P. M. Jordan, M. J. Gerl, C. Klose, L. Cantuti-Castelvetri, M. Bosch-Queralt, I. Levental, S. F. Lichtenthaler, O. Werz, M. Simons

Date Published: 26th Oct 2021

Publication Type: Journal

The pseudoprotease iRhom1 controls ectodomain shedding of membrane proteins in the nervous system.

Abstract (Expand)

Proteolytic ectodomain shedding of membrane proteins is a fundamental mechanism to control the communication between cells and their environment. A key protease for membrane protein shedding is ADAM17, … which requires a non-proteolytic subunit, either inactive Rhomboid 1 (iRhom1) or iRhom2 for its activity. While iRhom1 and iRhom2 are co-expressed in most tissues and appear to have largely redundant functions, the brain is an organ with predominant expression of iRhom1. Yet, little is known about the spatio-temporal expression of iRhom1 in mammalian brain and about its function in controlling membrane protein shedding in the nervous system. Here, we demonstrate that iRhom1 is expressed in mouse brain from the prenatal stage to adulthood with a peak in early postnatal development. In the adult mouse brain iRhom1 was widely expressed, including in cortex, hippocampus, olfactory bulb, and cerebellum. Proteomic analysis of the secretome of primary neurons using the hiSPECS method and of cerebrospinal fluid, obtained from iRhom1-deficient and control mice, identified several membrane proteins that require iRhom1 for their shedding in vitro or in vivo. One of these proteins was 'multiple-EGF-like-domains protein 10' (MEGF10), a phagocytic receptor in the brain that is linked to the removal of amyloid beta and apoptotic neurons. MEGF10 was further validated as an ADAM17 substrate using ADAM17-deficient mouse embryonic fibroblasts. Taken together, this study discovers a role for iRhom1 in controlling membrane protein shedding in the mouse brain, establishes MEGF10 as an iRhom1-dependent ADAM17 substrate and demonstrates that iRhom1 is widely expressed in murine brain.

Authors: J. Tushaus, S. A. Muller, J. Shrouder, M. Arends, M. Simons, N. Plesnila, C. P. Blobel, S. F. Lichtenthaler

Date Published: 6th Oct 2021

Publication Type: Journal

White matter aging drives microglial diversity.

Abstract (Expand)

Aging results in gray and white matter degeneration, but the specific microglial responses are unknown. Using single-cell RNA sequencing from white and gray matter separately, we identified white … matter-associated microglia (WAMs), which share parts of the disease-associated microglia (DAM) gene signature and are characterized by activation of genes implicated in phagocytic activity and lipid metabolism. WAMs depend on triggering receptor expressed on myeloid cells 2 (TREM2) signaling and are aging dependent. In the aged brain, WAMs form independent of apolipoprotein E (APOE), in contrast to mouse models of Alzheimer's disease, in which microglia with the WAM gene signature are generated prematurely and in an APOE-dependent pathway similar to DAMs. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin. Thus, WAMs may represent a potentially protective response required to clear degenerated myelin accumulating during white matter aging and disease.

Authors: S. Safaiyan, S. Besson-Girard, T. Kaya, L. Cantuti-Castelvetri, L. Liu, H. Ji, M. Schifferer, G. Gouna, F. Usifo, N. Kannaiyan, D. Fitzner, X. Xiang, M. J. Rossner, M. Brendel, O. Gokce, M. Simons

Date Published: 7th Apr 2021

Publication Type: Journal

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia.

Abstract (Expand)

Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent … pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1(-/-) microglia feature a striking accumulation of multivesicular bodies and impaired trafficking of lipids to lysosomes while lysosomal degradation function remains preserved. Molecular and functional defects were also detected in blood-derived macrophages of NPC patients that provide a potential tool for monitoring disease. Our study underscores an essential cell autonomous role for NPC1 in immune cells and implies microglial therapeutic potential.

Authors: A. Colombo, L. Dinkel, S. A. Muller, L. Sebastian Monasor, M. Schifferer, L. Cantuti-Castelvetri, J. Konig, L. Vidatic, T. Bremova-Ertl, A. P. Lieberman, S. Hecimovic, M. Simons, S. F. Lichtenthaler, M. Strupp, S. A. Schneider, S. Tahirovic

Date Published: 24th Feb 2021

Publication Type: Journal

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