Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CSN5 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration

ABSTRACT: Oligodendrocytes are the primary target of demyelinating disorders in the CNS, which may evolve in neurodegeneration. DNA damage and oxidative stress are considered key pathogenic events, but the underlying molecular mechanisms remain unclear. Moreover, comprehensive animal models are lacking or do not fully recapitulate human diseases, complicating the path to effective treatments. Here we report that mice with cell autonomous deletion of the COP9 signalosome component CSN5 (Jab1) in oligodendrocytes develop DNA damage and defective DNA repair in myelinating glial cells. Interestingly, oligodendrocytes lacking Jab1 expression undergo a senescence-like phenotype that fosters chronic inflammation and oxidative stress. These mutants develop progressive CNS demyelination, microglia inflammation and neurodegeneration, with severe motor deficits and premature death. Notably, blocking microglia inflammation did not prevent neurodegeneration; whereas, deletion of p21CIP1 but not p16INK4a pathway ameliorated the disease. We suggest that senescence is key to sustaining neurodegeneration in demyelinating disorders and might represent a new potential therapeutic target.

ORGANISM(S): Mus musculus

PROVIDER: GSE184573 | GEO | 2022/02/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

CSN5 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration

Project description:CSN5 deletion in oligodendrocytes causes senescence-induced inflammation and neurodegeneration

| PRJNA765202 | ENA

RNAseq data of brain cortex from mice at d10 post-microglia depletion and non-depleted controls

Project description:Previous studies have reported that microglia depletion leads to impairment of synapse formation and these cells rapidly repopulate from CNS progenitors. However, the impact of microglia depletion and repopulation on the long-term state of the CNS environment has not been characterized. Here, we found by RNA-seq analysis that acute and synchronous microglia depletion results in a type 1-interferon inflammatory signature in degenerating somatosensory cortex in microglia-depleted mice. Transcriptomic and mass cytometry analysis of repopulated microglia demonstrates an interferon regulatory factor 7-driven activation state. Minocycline and anti-IFNAR1 antibody treatment attenuate the CNS type-1 interferon-driven inflammation and restore microglia homeostasis. Together, we found that acute microglia ablation induces a type-1 interferon activation state of grey matter microglia associated with acute neurodegeneration.

2018-06-08 | GSE115447 | GEO

Proteomic and lipidomic profiling of demyelinating lesions identifies fatty acids as modulators in inflammation resolution

Project description:After demyelinating injury of the central nervous system, resolution of the mounting acute innate inflammation is crucial for the initiation of a regenerative response. To identify factors in lesion recovery after demyelination injury, we used a toxin-induced model, in which a single dose of lysolecithin is injected into the corpus callosum to induce a focal demyelinating lesion. Afterwards, we investigated the proteome of demyelinating lesions at different time points post injection (dpi) in a time resolved manner. Lesion sites were excised analyzed from different mice at 0 dpi, without lysolecithin injection, as well as lysolecithin treated mice at 3 dpi, 7 dpi, and 14 dpi. Overall, immune cell migration, especially infiltration of microglia and macrophages, as well as fatty acid metabolism are playing crucial roles for the immidiate response, repair and finally lesion recovery. Additionally, Using lipidomics and eicosanoidomics, we identified bioactive lipids in the resolution phase of inflammation with a marked induction of n-3 polyunsaturated fatty acids. Using fat-1 transgenic mice, which convert n-6 fatty acids to n-3 fatty acids, we found that reduction of the n-6/n-3 ratio facilitates inflammation resolution. In addition, we observed accelerated inflammation resolution and enhanced generation of oligodendrocytes in aged mice when n-3 fatty acids are shuttled to the brain. Thus, n-3 fatty acids and eicosanoids, their oxidized bioactive products, enhance lesion recovery and may therefore provide the basis for novel pro-regenerative medicines of demyelinating diseases in the central nervous system.

2021-09-30 | PXD024891 | Pride

Pharmacologic inhibition of EphB3 receptor kinase ameliorates EAE

Project description:To evaluate the potential of EphB3 as a therapeutic target during CNS inflammation, we induced EAE in B6 WT mice and starting at the peak of the disease we initiated treatment with A38 administered. A38 administration ameliorated EAE, and the transcriptional analysis of the astrocytes and microglia revealed the decreased expression of genes associated to inflammation and neurodegeneration.

2022-02-25 | GSE149135 | GEO

Exploring a novel target of levetiracetam to suppress microglial inflammatory reaction

Project description:Microglia are macrophages-like cells in the central nervous system (CNS) harboring important roles such as synaptic organization, phagocytosis of debris and apoptotic cells, and repairing damaged tissue. Microglial function is tightly controlled, but under certain pathological conditions, activated microglia can induce excess inflammation which injure live cells in the CNS. Therefore, suppression of microglia is a fundamental strategy to treat CNS disorders. We have previously shown that the antiepileptic drug levetiracetam (LEV) inhibits microglia activation, but mechanism remains unclear. The purpose of this study is to identify a target of LEV to suppress microglial activity.

2021-07-28 | GSE180828 | GEO

Eph Receptor B3/EphrinB3 signaling impact CNS pathology during EAE

Project description:We aimed to investigate the role of EphB3 and EfnB3 on the regulation of astrocyte and microglial responses in the context of CNS inflammation, we KD Efnb3 in microglia or EphB3 in astrocytes both resulting in a comparable amelioration of EAE. The transcriptional analysis of the two cell types revealed the decreased expression of genes associated to inflammation and neurodegeneration in both KD conditions.

2022-02-25 | GSE149052 | GEO

Opposite roles for astrocytes in developmental myelination and early myelin repair

Project description:Understanding the regulation of oligodendrocyte development and myelination in the central nervous system (CNS) is essential, not only to facilitate myelin repair but also to define the role of oligodendrocytes in maintaining axonal integrity. In vitro studies have implicated astrocytes in influencing multiple aspects of oligodendrocytes and their precursors, however the in vivo role of astrocytes in myelination and myelin repair remain poorly defined. We show that astrocyte ablation during postnatal spinal cord development resulted in a concomitant delay in myelination, demonstrating a critical role for astrocytes in promoting developmental myelination. By contrast, in the adult CNS, localized ablation of astrocytes 2 days after a demyelinating insult resulted in increased numbers of oligodendrocytes and accelerated remyelination in both the spinal cord and the corpus callosum. Microarray analysis reveals astrocytic NF-kB signaling pathway as a major contributor to pathological events occurring after demyelination. We suggest that the localized functions of astrocytes are fundamentally different during developmental myelination and myelin repair. Astrocytes are critical for developmental myelination, however in a demyelinating environment they are detrimental to myelin repair.

2017-08-01 | GSE60276 | GEO

Pro-inflammatory activity following demyelinating injury is required for phagocytic function and oligodendrocyte formation

Project description:Remyelination can occur naturally in demyelinating lesions, but often fails in human demyelinating diseases such as multiple sclerosis (MS). The function of the innate immune system is essential for the regenerative response, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory nuclear factor κB (NF-κB) dependent activation occurs in phagocytes rapidly after myelin injury. We found that the pro-inflammatory response depends on myeloid differentiation primary response 88 (MyD88), the canonical adaptor for inflammatory signaling pathways downstream of toll-like receptors (TLRs). MyD88-deficient mice and zebrafish were impaired not only in the degradation of myelin debris, but also in initiating the generation of new oligodendrocytes for myelin repair. We identified reduced generation of tumor necrosis factor-α (TNF-α) in lesions of MyD88-deficient animals, a pro-inflammatory molecule that was able to induce the generation of new oligodendrocytes. Our study shows that pro-inflammatory phagocytic signaling is an evolutionary conserved mechanism necessary for degrading myelin debris, essential for inflammation resolution, and for initiating the secretion of pro-inflammatory myelin repair molecules.

2020-02-17 | PXD014625 | Pride

Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution

Project description:Microglia play critical roles in neural development and homeostasis. They are also implicated in neurodegenerative and neuroinflammatory diseases of the central nervous system (CNS). However, little is known about the presence of spatially and temporally restricted subclasses of microglia during CNS development and disease. Here, we combined massively parallel single-cell analysis, single-molecule FISH, advanced immunohistochemistry and computational modelling to comprehensively characterize novel microglia subclasses, which were transcriptionally different from perivascular macrophages, in up to six different CNS regions during development and diseases. Single-cell analysis revealed specific time- and region-dependent microglia subtypes during homeostasis. In contrast, demyelinating and neurodegenerative diseases evoked context-dependent microglia subtypes with distinct molecular hallmarks and diverse cellular kinetics. Finally, diverse microglia subsets were also identified in normal and diseased human brains. Our data provide new insights into the CNS endogenous immune system during development, health and perturbations.

2019-02-13 | GSE124335 | GEO

Efficient strategies for microglia replacement in the central nervous system

Project description:Microglia are important immune cells in the central nervous system (CNS). Dysfunctions of gene-deficient microglia contribute to the development and progression of multiple CNS diseases. Microglia replacement by nonself cells has been proposed to treat microglia associated disorders. However, most of attempts are failed due to low replacement efficiencies, such as with the traditional bone marrow transplantation approach. In this study, we develop three efficient strategies for microglia replacement: microglia replacement by bone marrow transplantation (mrBMT), microglia replacement by peripheral blood (mrPB) and microglia replacement by microglia transplantation (mrMT). mrBMT and mrPB allow microglia-like cells to efficiently replace resident microglia in the whole CNS. On the other hand, mrMT achieves microglia replacement in brain regions of interest. In summary, the present study offers effective tactics for microglia replacement with diverse application scenarios, which potentially opens up a window on treating microglia-associated CNS disorders.

2020-07-31 | GSE155499 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data