Search results for "demyelinating diseases"
showing 10 items of 28 documents
NG2-positive cells in CNS function and the pathological role of antibodies against NG2 in demyelinating diseases
2005
NG2 is expressed by a variety of immature glia in the CNS including oligodendrocyte progenitor cells, paranodal astrocytes and perisynaptic glia. The protein has a large extracellular domain with two LNS/Lam G domains at the N-terminus and a short intracellular tail with a PDZ-recognition domain at the C-terminus. Experiments suggest that the protein plays a role in migration. The PDZ protein GRIP was identified as an intracellular binding partner of NG2 in immature glial cells. A complex is formed between GRIP, NG2 and the AMPA class of glutamate receptors: this may position these glial receptors towards sites of neuronal glutamate release at synapses and during myelination. Identification…
T helper cell- and CD40-dependent germline IgM prevents chronic virus-induced demyelinating disease
2012
Generation of antiviral IgM is usually considered as a marker of a short-lived initial antibody response that is replaced by hypermutated and more-efficient IgG. However, once viruses have established a particular niche for their persistence (e.g., within the CNS), the immune system has to specifically mobilize a broad range of antimicrobial effectors to contain the pathogen in the long term. Infection of the CNS with the mouse hepatitis virus (MHV) provides a unique model situation in which the extent of inflammatory CNS disease is determined by the balance between antiviral immune control, viral replication, and immune-mediated damage. We show here that whereas antibody- or B cell-defici…
Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis.
2005
Abstract In experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, immunization with myelin Ags leads to demyelination and paralysis. To investigate which molecules are crucial for the pathogenesis of EAE, we specifically assessed the roles of the death receptors Fas and TNF-R1. Mice lacking Fas expression in oligodendrocytes (ODCs) were generated and crossed to TNF-R1-deficient mice. To achieve specific deletion of a loxP-flanked fas allele in ODCs, we generated a new insertion transgene, expressing the Cre recombinase specifically in ODCs. Fas inactivation alone as well as the complete absence of TNF-R1 protected mice partially from EAE induced by the imm…
BLBP-expression in astrocytes during experimental demyelination and in human multiple sclerosis lesions
2011
Several lines of evidence indicate that remyelination represents one of the most effective mechanisms to achieve axonal protection. For reasons that are not yet understood, this process is often incomplete or fails in multiple sclerosis (MS). Activated astrocytes appear to be able to boost or inhibit endogenous repair processes. A better understanding of remyelination in MS and possible reasons for its failure is needed. Using the well-established toxic demyelination cuprizone model, we created lesions with either robust or impaired endogenous remyelination capacity. Lesions were analyzed for mRNA expression levels by Affymetrix GeneChip® arrays. One finding was the predominance of immune a…
Increased cortical curvature reflects white matter atrophy in individual patients with early multiple sclerosis
2014
Objective White matter atrophy occurs independently of lesions in multiple sclerosis. In contrast to lesion detection, the quantitative assessment of white matter atrophy in individual patients has been regarded as a major challenge. We therefore tested the hypothesis that white matter atrophy (WMA) is present at the very beginning of multiple sclerosis (MS) and in virtually each individual patient. To find a new sensitive and robust marker for WMA we investigated the relationship between cortical surface area, white matter volume (WMV), and whole-brain-surface-averaged rectified cortical extrinsic curvature. Based on geometrical considerations we hypothesized that cortical curvature increa…
In toxic demyelination oligodendroglial cell death occurs early and is FAS independent
2010
Oligodendroglial cell death is a frequent phenomenon of many neurological diseases, e.g. in demyelinating diseases such as multiple sclerosis (MS). The underlying mechanisms are largely unknown. Here, we demonstrate that in the toxic demyelination cuprizone model, oligodendroglial cell death and downregulation of myelin genes start days after initiation of the cuprizone diet and weeks before demyelination is obvious. In early – but not in later – stages, dying oligodendrocytes express activated caspase 3, suggesting a switch from classical apoptotic pathways to caspase 3-independent mechanisms during the course of the cuprizone diet. The expression level of FAS in the corpus callosum, a cel…
Quantitative and integrative proteome analysis of peripheral nerve myelin identifies novel myelin proteins and candidate neuropathy loci
2011
Peripheral nerve myelin facilitates rapid impulse conduction and normal motor and sensory functions. Many aspects of myelin biogenesis, glia–axonal interactions, and nerve homeostasis are poorly understood at the molecular level. We therefore hypothesized that only a fraction of all relevant myelin proteins has been identified so far. Combining gel-based and gel-free proteomic approaches, we identified 545 proteins in purified mouse sciatic nerve myelin, including 36 previously known myelin constituents. By mass spectrometric quantification, the predominant P0, periaxin, and myelin basic protein constitute 21, 16, and 8% of the total myelin protein, respectively, suggesting that their relat…
Autoreactive Antibodies and Loss of Retinal Ganglion Cells in Rats Induced by Immunization with Ocular Antigens
2011
PURPOSE In an experimental autoimmune animal model, retinal ganglion cell (RGC) loss was induced through immunization with glaucoma-related antigens. The target of this study was to investigate the pathomechanism behind this decline and the serum antibody reactivity against ocular and neuronal tissues after immunization with glaucoma- and non-glaucoma-associated antigens. METHODS Rats immunized with optic nerve antigen homogenate (ONA) or keratin (KER) were compared to control rats (CO). Intraocular pressure (IOP) was measured, and the fundi were examined regularly. Four weeks afterward, cells were counted in retinal flat mounts. Retina, optic nerve, and brain sections from healthy animals …
Biallelic mutations in neurofascin cause neurodevelopmental impairment and peripheral demyelination
2019
See Karakaya and Wirth (doi:10.1093/brain/awz273) for a scientific commentary on this article. Neurofascin (NFASC) isoforms are immunoglobulin cell adhesion molecules involved in node of Ranvier assembly. Efthymiou et al. identify biallelic NFASC variants in ten unrelated patients with a neurodevelopmental disorder characterized by variable degrees of central and peripheral involvement. Abnormal expression of Nfasc155 is accompanied by severe loss of myelinated fibres.
The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease
2001
We identified three distinct mutations and six mutant alleles in GDAP1 in three families with axonal Charcot-Marie-Tooth (CMT) neuropathy and vocal cord paresis, which were previously linked to the CMT4A locus on chromosome 8q21.1. These results establish the molecular etiology of CMT4A (MIM 214400) and suggest that it may be associated with both axonal and demyelinating phenotypes.