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glial cell membrane [keywords]
- Photoreceptor degeneration, structural remodeling and glial activation: a morphological study on a genetic mouse model for pericyte deficiency. [JOURNAL ARTICLE]
- Neuroscience 2014 Sep 12.
Interaction between pericytes and endothelial cells via PDGF-B (platelet derived growth factor B) signaling is critical for the development of the retinal microvasculature. The PDGF-B retention motif controls the spatial distribution range of the growth factor in the vicinity of its producing endothelial cells allowing its recognition by PDGFR-β (PDGF receptor beta) carrying pericytes; this promotes recruitment of pericytes to the vascular basement membrane. Impairment of the PDGF-B signaling mechanism causes development of vascular abnormalities, and in the retina this consequently leads to defects in the neurological circuitry. The vascular pathology in the pdgf-b(ret/ret) (PDGF-B retention motif knockout) mouse retina has been previously reported; our study investigates the progressive neuronal defects and changes in the retinal morphology of this pericyte deficient mouse model. Immunohistochemical analysis revealed retinal injuries to occur as early as postnatal day (P)10 with substantial damage progressing from P15 and onwards. Vascular abnormalities were apparent from P10, however, prominent neuronal defects were mostly observed from P15, beginning with the compromised integrity of the laminated retinal structure characterized by the presence of rosettes and focally distorted regions. Photoreceptor degeneration was observed by loss of both rod and cone cells, including the disassembly and altered structure of their synaptic terminals. Significant shortening of cone outer segments was observed from P10 and later stages; however, decrease in cone density was only observed at P28. Disorganization and dendrite remodeling of rod bipolar cells also added to the diminished neural and synaptic integrity. Moreover, in response to retinal injuries, Müller and microglial cells were observed to be in the reactive phenotype from P15 and onwards. Such sequence of events indicates that the pdgf-b(ret/ret) mouse model displays a short time frame between P10 to P15, during which the retina shifts to a retinopathic phase by the development of prominently altered morphological features.
- Testing the effects of the dye Acid violet-17 on retinal function for an intraocular application in vitreo-retinal surgery. [JOURNAL ARTICLE]
- Graefes Arch Clin Exp Ophthalmol 2014 Sep 14.
To facilitate epiretinal or inner limiting membrane peeling, dyes like Indocyanine Green (ICG) as well as Trypan Blue (TB) were used so far. However, toxic effects on the retina were described for both dyes. The aim of our study was to investigate the effects of a novel vital dye Acid violet-17 (AV-17) on retinal histology and function to assess a possible application in vitreo-retinal surgery.AV-17 was dissolved in a solvent with heavy water. An electroretinogram was recorded on perfused bovine retina. After reaching stable b-wave amplitudes, AV-17 (0.125-0.5 mg/ml) or the solvent was applied epiretinally for 30-300 seconds. The b-wave amplitudes were recorded before, during, and after treatment. Cultures of bovine retina were incubated for 30 or 300 seconds with the dye or solvent and processed for live/dead staining, immunohistochemistry, and immunoblotting.Reductions of the b-wave amplitudes were observed directly after the exposure to AV-17, which were rapidly and completely reversible within the recovery period for all exposure times at the concentrations of 0.125 and 0.25 mg/ml as opposed to the partial recovery after exposure to 0.5 mg/ml. A high degree of damage in the ganglion cell layer (GCL) and glial reactivity were detected at the concentrations of 0.25 and 0.5 mg/ml but not after exposure to lower concentrations or the solvent.Application of AV-17 at a concentration of up to 0.125 mg/ml was well tolerated in terms of retinal function, survival in the GCL, and glial reactivity whereas higher concentrations are not recommended.
- Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy. [JOURNAL ARTICLE]
- Acta Neuropathol Commun 2014 Sep 11; 2(1):136.
p25¿/tubulin polymerization promoting protein (TPPP) is an oligodendroglial protein that plays crucial roles including myelination, and the stabilization of microtubules. In multiple system atrophy (MSA), TPPP is suggested to relocate from the myelin sheath to the oligodendroglial cell body, before the formation of glial cytoplasmic inclusions (GCIs), the pathologic hallmark of MSA. However, much is left unknown about the re-distribution of TPPP in MSA. We generated new antibodies against the N- and C-terminus of TPPP, and analyzed control and MSA brains, including the brain of a familial MSA patient carrying homozygous mutations in the coenzyme Q2 gene (COQ2). In control brain tissues, the TPPP was localized not only in the cytoplasmic component of the oligodendroglia including perinuclear cytoplasm and peripheral processes in the white matter, but also in the nucleus of a fraction (62.4%) of oligodendroglial cells. Immunoelectron microscopic analysis showed TPPP in the nucleus and mitochondrial membrane of normal oligodendroglia, while western blot also supported its nuclear and mitochondrial existence. In MSA, the prevalence of nuclear TPPP was 48.6% in the oligodendroglia lacking GCIs, whereas it was further decreased to 19.6% in the oligodendroglia with phosphorylated ¿-synuclein (p¿-syn)-positive GCIs, both showing a significant decrease compared to controls (62.4%). In contrast, TPPP accumulated in the perinuclear cytoplasm where mitochondrial membrane (TOM20 and cytochrome C) and fission (DRP1) proteins were often immunoreactive. We conclude that in MSA-oligodendroglia, the TPPP is reduced, not only in the peripheral cytoplasm, but also in the nucleus and relocated to the perinuclear cytoplasm.
- Proteomics in neurodegenerative diseases: Methods for obtaining a closer look at the neuronal proteome. [JOURNAL ARTICLE]
- Proteomics Clin Appl 2014 Sep 5.
The analysis of brain function in normal aging and neurodegenerative, psychiatric and neurological diseases has long been a subject of interest and has historically been investigated through descriptive analysis of macroscopic or microscopic observations. It is now possible to characterize brain cells, such as neurons and glial cells, or even their subcellular components, at the molecular level. This ability enables researchers to more closely examine brain cell-specific molecular pathways to elucidate distinct brain functions. Furthermore, the analysis of neuronal maintenance and disease-causing effects is a central component of neurological investigations, which include proteomic approaches. Proteomics allows the identification of thousands of proteins through descriptive and comparative analyses and can provide a detailed overview of a distinct cellular state. Such analyses often require the isolation of individual cell types or subcellular components to investigate specific questions. This review provides an overview of the currently applied state-of-the-art prefractionation strategies in this field. This article is protected by copyright. All rights reserved.
- β-Caryophyllene protects the C6 glioma cells against glutamate-induced excitotoxicity through the Nrf2 pathway. [JOURNAL ARTICLE]
- Neuroscience 2014 Sep 4.
β-Caryophyllene (BCP), a natural bicyclic sesquiterpene present in several essential oils, displays analgesic and anti-inflammatory properties in vitro and in vivo. Astrocytes are a major class of glial cells that regulate extracellular ion balance, repair and scarring processes in the CNS following neuroinflammatory conditions and traumatic injuries. This study sought to determine the protective effect of BCP against glutamate (Glu)-induced cytotoxicity in the C6 glioma cell line on neurochemical parameters as well as their biochemical mechanism. Glu increases intracellular reactive oxygen species (ROS) production and induces mitochondrial dysfunction as well as decreasing antioxidant defenses such as glutathione (GSH) and glutathione peroxidase activity. BCP prevented C6 cells from Glu-induced cytotoxicity by modulating the cellular antioxidant response, mainly by inhibiting ROS production and reestablishing the mitochondrial membrane potential (Δψm). Moreover, BCP per se induced the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) which was reflected by improvement in the cellular GSH antioxidant system. Taken together, our results suggest that cytoprotective effects of BCP were mediated by the amelioration of cellular antioxidant responses via Nrf2 activation, which is, in part, dependent of cannabinoid receptor type 2 (CB2R) activation. This functional nonpsychoactive CB2R ligand, could represent an important molecule for protection of glial cells against oxidative stress induced by glutamate.
- Bradykinin enhances invasion of malignant glioma into the brain parenchyma by inducing cells to undergo amoeboid migration. [JOURNAL ARTICLE]
- J Physiol 2014 Sep 5.
The molecular and cellular mechanisms governing cell motility and directed migration in response to the neuropeptide bradykinin are largely unknown. Here, we demonstrate that human glioma cells whose migration is guided by bradykinin generate bleb-like protrusions. We found that activation of the B2 receptor leads to a rise in free Ca(2+) from internal stores that activate actomyosin contraction and subsequent cytoplasmic flow into protrusions forming membrane blebs. Furthermore Ca(2+) activates Ca(2+) dependent K(+) and Cl(-) channels, which participate in bleb regulation. Treatment of gliomas with bradykinin in situ increased glioma growth by increasing the speed of cell migration at the periphery of the tumor mass. To test if bleb formation is relevant for bradykinin promoted glioma invasion we blocked glioma migration by blebbistatin a blocker of myosin kinase II, which is necessary for proper bleb retraction. Our findings suggest a pivotal role of bradykinin during glioma invasion by stimulating amoeboid migration of glioma cells. This article is protected by copyright. All rights reserved.
- GRAF1a is a brain-specific protein promoting lipid droplet clustering and growth and enriched at lipid droplet junctions. [JOURNAL ARTICLE]
- J Cell Sci 2014 Sep 4.
Lipid droplets are found in all cell types. Normally present at low levels in the brain, they accumulate in tumours and are associated with neurodegenerative diseases. However, little is known about the mechanisms controlling their homeostasis in the brain. We have found that the longest GRAF1 isoform, GRAF1a, is enriched in the brains of neonates. Endogenous GRAF1a is found on lipid droplets in oleic-acid fed primary glial cells. Exclusive localization requires a GRAF1a-specific hydrophobic segment and two membrane-binding regions, a BAR and a PH domain. Overexpression of GRAF1a promotes lipid droplet clustering, inhibits droplet mobility and severely perturbs lipolysis following the chase of fatty acid-overloaded cells. Under these conditions, GRAF1a concentrates at the interface between lipid droplets. Although GRAF1 knockout mice do not show any gross abnormal phenotype, the total lipid droplet volume that accumulates in GRAF1(-/-) primary glia upon incubation with fatty acids is reduced compared to GRAF1(+/+) cells. These results provide additional insights into the mechanisms contributing to lipid droplet growth in non-adipocyte cells, and suggest that proteins with membrane sculpting BAR domains play a role in droplet homeostasis.
- Chemoresistance in high-grade gliomas: relevance of adenosine signalling in stem-like cells of glioblastoma multiforme. [JOURNAL ARTICLE]
- Curr Drug Targets 2014 Aug 25.
Glioblastoma multiforme (GBM) is the most common glial cell-derived brain tumour, with one of the worst prognosis among all cancers. GBM cells are infiltrative and extremely resistant to radio- and chemotherapy, which inevitably leads to recurrence after surgical resection. These inherent GBM properties are the reasons patient treatment has not seen major improvements in decades. Studies have consistently shown that glioblastoma stem-like cells (GSCs) are responsible for the tumourigenic properties in the GBM population. In fact, their self-renewal and proliferative potential are required for tumour growth, and their extreme chemoresistance leads to early recurrence of this tumor. Among those mechanisms associated with chemoresistance and having the greatest clinical impact in cancer treatment, are the activities of plasma membrane transporters that extrude antitumour drugs from the cell, thus notably decreasing the pharmacological efficiency of these drugs. The multiple drug resistance associated protein-1 (Mrp1) transporter has been shown to be particularly important in GBM, as inhibition of Mrp1 activity notably chemosensitises cells to antiproliferative drugs. As current therapeutic options for GBM offer only a poor improvement in overall survival rate, alternative strategies for overcoming tumour resistance are urgently sought after. To this end, it is of major clinical relevance to know more about the endogenous modulators that control Mrp1 expression within the pathological environment of the tumour. This review describes the particular properties of glioblastoma cells that overcome multimodal therapy and relapse, with an emphasis on the microenvironmental tumour properties that influence the chemoresistance phenotype to antiproliferative drugs. We also discuss alternative methods of reversal of Mrp1-mediated chemoresistance in these cells by targeting extracellular adenosine production or signalling through particular plasma membrane receptors.
- Clinical and histological characteristics of canine ocular gliovascular syndrome. [JOURNAL ARTICLE]
- Vet Ophthalmol 2014 Sep 1.
To characterize the clinical, diagnostic, and histopathologic findings in dogs with canine ocular gliovascular syndrome (COGS).The archives at the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) were used to identify eyes with COGS. Histopathological inclusion criteria included: a neovascular membrane extending from the optic nerve head or retina, clusters of spindle cells lacking vascularization within the vitreous, and histological signs of glaucoma. Special and immunohistochemical (IHC) staining techniques were performed. Clinical data, treatments, and outcomes were obtained from case records and information provided by submitting veterinarians.Thirty-seven eyes of 36 dogs were identified with COGS. The average age at diagnosis was 8.8 years (±2.2). The relative risk for a Labrador retriever affected by COGS was significantly greater (9.3 times) (P < 0.0001) when compared to all other dog breeds within the COPLOW database. Most dogs presented with hyphema and secondary glaucoma; average intraocular pressure was 39 mmHg (±19). Average time to enucleation or evisceration was 27 days. Vitreal cells stained positive with IHC for glial fibrillary acidic protein in 14 of 17 globes, and vascular endothelial growth factor was expressed in the vitreal cells in five of five globes.We have defined a syndrome associated with vitreal glial cell aggregates and neovascular proliferation from the optic nerve or retina, which leads to neovascular glaucoma. The inflammation and secondary glaucoma resulting from this syndrome appear poorly responsive to conventional medical therapies. The exact etiology of COGS remains undetermined, but a systemic etiology is unlikely.
- Shedding of NG2 by MMP-13 Attenuates Anoikis. [JOURNAL ARTICLE]
- DNA Cell Biol 2014 Aug 28.
Disruption of cell-matrix interactions can lead to anoikis-apoptosis due to loss of matrix contacts. We previously showed that Nerve/glial antigen 2 (NG2) is a novel anoikis receptor. Specifically, overexpression of NG2 leads to anoikis propagation, whereas its suppression leads to anoikis attenuation. Interestingly, NG2 expression decreases in late anoikis, suggesting that NG2 reduction is also critical to this process. Thus, we hypothesized that NG2 undergoes cleavage to curtail anoikis propagation. Further, since matrix metalloproteinases (MMPs) cleave cell surface receptors, play a major role in modulating apoptosis, and are associated with death receptor cleavage during apoptosis, we further hypothesized that cleavage of NG2 could be mediated by MMPs to regulate anoikis. Indeed, anoikis conditions triggered release of the NG2 extracellular domain into condition media during late apoptosis, and this coincided with increased MMP-13 expression. Treatment with an MMP-13 inhibitor and MMP-13 siRNA increased anoikis, since these treatments blocked NG2 release. Further, NG2-positive cells exhibited increased anoikis upon MMP-13 inhibition, whereas MMP-13 inhibition did not increase anoikis in NG2-null cells, corroborating that retention of NG2 on the cell membrane is critical for sustaining anoikis, and its cleavage for mediating anoikis attenuation. Similarly, NG2 suppression with siRNA inhibited NG2 release and anoikis. In contrast, MMP-13 overexpression or exogenous MMP-13 reduced anoikis by more effectively shedding NG2. In conclusion, maintenance of NG2 on the cell surface promotes anoikis propagation, whereas its shedding by MMP-13 actions attenuates anoikis. Given that these findings are derived in the context of periodontal ligament fibroblasts, these data have implications for periodontal inflammation and periodontal disease pathogenesis.