Publications by authors named "Sebastian Werneburg"

The pathological role of interferon signaling is emerging in neuroinflammatory disorders, yet, the specific role of Interferon Regulatory Factor 3 (IRF3) in neuroinflammation remains poorly understood. Here, we show that global IRF3 deficiency delays TLR4-mediated signaling in microglia and attenuates the hallmark features of LPS-induced inflammation such as cytokine release, microglial reactivity, astrocyte activation, myeloid cell infiltration, and inflammasome activation. Moreover, expression of a constitutively active IRF3 (S388D/S390D: IRF3-2D) in microglia induces a transcriptional program reminiscent of the Activated Response Microglia and the expression of genes associated with Alzheimer's disease, notably apolipoprotein-e.

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The pathological role of interferon signaling is emerging in neuroinflammatory disorders, yet, the specific role of Interferon Regulatory Factor 3 (IRF3) in neuroinflammation remains poorly understood. Here, we show that global IRF3 deficiency delays TLR4-mediated signaling in microglia and attenuates the hallmark features of LPS-induced inflammation such as cytokine release, microglial reactivity, astrocyte activation, myeloid cell infiltration, and inflammasome activation. Moreover, expression of a constitutively active IRF3 (S388D/S390D:IRF3-2D) in microglia induces a transcriptional program reminiscent of the Activated Response Microglia and the expression of genes associated with Alzheimer's Disease, notably Lastly, using bulk-RNAseq of IRF3-2D brain myeloid cells, we identified Z-DNA binding protein-1 as a target of IRF3 that is relevant across various neuroinflammatory disorders.

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While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS.

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Article Synopsis
  • - The study analyzes over 25,000 rare genetic variants in noncoding regions related to amyotrophic lateral sclerosis (ALS) using data from more than 6,000 ALS patients and over 70,000 controls.
  • - Researchers found that specific variants in the 3' untranslated region of the IL18RAP gene are more common in non-ALS individuals, significantly lowering their risk of developing ALS by five times.
  • - These IL18RAP variants enhance the survival of motor neurons by reducing neuroinflammation, highlighting the critical role of noncoding regions in genetic studies related to diseases like ALS.
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Multiple sclerosis (MS) is a demyelinating, autoimmune disease of the central nervous system. While work has focused on myelin and axon loss in MS, less is known about mechanisms underlying synaptic changes. Using postmortem human MS tissue, a preclinical nonhuman primate model of MS, and two rodent models of demyelinating disease, we investigated synapse changes in the visual system.

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Multiple sclerosis (MS) is a neuroinflammatory disease with a relapsing-remitting disease course at early stages, distinct lesion characteristics in cortical grey versus subcortical white matter and neurodegeneration at chronic stages. Here we used single-nucleus RNA sequencing to assess changes in expression in multiple cell lineages in MS lesions and validated the results using multiplex in situ hybridization. We found selective vulnerability and loss of excitatory CUX2-expressing projection neurons in upper-cortical layers underlying meningeal inflammation; such MS neuron populations exhibited upregulation of stress pathway genes and long non-coding RNAs.

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Microglia have recently been recognized as key regulators of synapse development, function, and plasticity. Critical to progressing the field is the identification of molecular underpinnings necessary for microglia to carry out these important functions within neural circuits. Here, we focus a review specifically on roles for microglial cytokine signaling within developing and mature neural circuits.

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Polysialic acid is a glycan modification of the neural cell adhesion molecule (NCAM) produced by the polysialyltransferases ST8SIA2 and ST8SIA4. Polysialic acid has been detected in multiple sclerosis plaques, but its beneficial or adverse role in remyelination is elusive. Here, we show that, despite a developmental delay, myelination at the onset and during cuprizone-induced demyelination was unaffected in male or mice.

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Human pluripotent stem cells (hPSCs), both embryonic (hESCs) and induced (hiPSCs), can be differentiated into derivatives of the three germ layers and are promising tools in regenerative medicine. Cardiovascular diseases are the top-ranking cause of premature death worldwide, and cell replacement therapies based on in vitro differentiated cardiomyocytes might provide a promising perspective to cure patients in the future. The molecular processes during hPSC cardiomyogenesis are far from being fully understood, and we thus have focused here on characterizing the proteome along hESC in vitro differentiation into cardiomyocytes (CMs).

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ST8SIA2 is a polysialyltransferase that attaches polysialic acid to the glycoproteins NCAM1 and CADM1. Polysialylation is involved in brain development and plasticity. ST8SIA2 is a schizophrenia candidate gene, and St8sia2 mice exhibit schizophrenia-like behavior.

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Sialic acids (Sias) are abundant terminal modifications of protein-linked glycans. A unique feature of Sia, compared with other monosaccharides, is the formation of linear homo-polymers, with its most complex form polysialic acid (polySia). Sia and polySia mediate diverse biological functions and have great potential for therapeutic use.

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Microglia are tissue macrophages and mediators of innate immune responses in the brain. The protein-modifying glycan polysialic acid (polySia) is implicated in modulating microglia activity. Cultured murine microglia maintain a pool of Golgi-confined polySia, which is depleted in response to lipopolysaccharide (LPS)-induced activation.

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Oligodendrocyte precursor cells (OPCs) are the progenitors of myelinating oligodendrocytes in brain development and repair. Successful myelination depends on the control of adhesiveness during OPC migration and axon contact formation. The decoration of cell surface proteins with the glycan polysialic acid (polySia) is a key regulatory element of OPC interactions during development and under pathological conditions.

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NG2 cells comprise a heterogeneous precursor population but molecular markers distinguishing between the assumed NG2 cell subpopulations are lacking. Previously, we described that a subfraction of the synaptic cell adhesion molecule SynCAM 1 is modified with the glycan polysialic acid (polySia) in NG2 cells. As for its major carrier, the neural cell adhesion molecule NCAM, polySia attenuates SynCAM 1 adhesion.

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The glycan polysialic acid is well-known as a unique posttranslational modification of the neural cell adhesion molecule NCAM. Despite remarkable acceptor specificity, however, a few other proteins can be targets of polysialylation. Here, we recapitulate the biosynthesis of polysialic acid by the two polysialyltransferases ST8SIA2 and ST8SIA4 and highlight the increasing evidence that variation in the human ST8SIA2 gene is linked to schizophrenia and possibly other neuropsychiatric disorders.

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The polysialic acid (polySia) modification of the neural cell adhesion molecule NCAM is a key regulator of cell migration. Yet its role in NCAM-dependent or NCAM-independent modulation of motility and cell-matrix adhesion is largely unresolved. Here, we demonstrate that loss of polySia attenuates tumour cell migration and augments the number of focal adhesions in a cell-cell contact- and NCAM-dependent manner.

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