Excess glutamate secreted from astrocytes drives upregulation of P-glycoprotein in endothelial cells in amyotrophic lateral sclerosis.

In this study, we found that glutamate, which is abnormally secreted by mutant SOD1 and sporadic ALS astrocytes, drives upregulation of P-gp expression and activity levels in endothelial cells via activation of N-Methyl-D-Aspartic acid (NMDA) receptors. Surprisingly, astrocyte-secreted glutamate regulation of endothelial P-gp levels is not a mechanism shared by all forms of ALS. C9orf72-ALS astrocytes had no effect on endothelial cell P-gp expression and did not display increased glutamate secretion. Utilizing an optimized in vitro human BBB model consisting of patient-derived induced pluripotent stem cells, we showed that co-culture of endothelial cells with patient-derived astrocytes increased P-gp expression levels and transport activity, which was significantly reduced when endothelial cells were incubated with the NMDAR antagonist, MK801. Overall, our findings unraveled a complex molecular interplay between astrocytes of different ALS genotypes and endothelial cells potentially occurring in disease that could differentially impact ALS prognosis and efficacy of pharmacotherapies. PMID: 30974102 [PubMed - as supplied by publisher]
Source: Experimental Neurology - Category: Neurology Authors: Tags: Exp Neurol Source Type: research

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We report rare/novel missense variants from 154 Indian ALS patients, identified through targeted sequencing of 25 ALS-associated genes. As pathogenic variants could explain only a small percentage of ALS pathophysiology in our cohort, we investigated the frequency of tolerated and benign novel/rare variants, which could be potentially ALS susceptible. These variants were identified in 5.36% (8/149) of sporadic ALS (sALS) cases; with one novel variant each inERBB4,SETX,DCTN1, andMATR3; four rare variants, one each inPON2 andANG and two different rare variants inSETX. Identified variants were either absent or present at extr...
Source: Neurogenetics - Category: Genetics & Stem Cells Source Type: research
FUS and EWSR1 are RNA-binding proteins with prion-like domains (PrLDs) that aggregate in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The FUS and EWSR1 genes are also prone to chromosomal translocation events, which result in aberrant fusions between portions of the PrLDs of FUS and EWSR1 and the transcription factors CHOP and FLI. The resulting fusion proteins, FUS-CHOP and EWS-FLI, drive aberrant transcriptional programs that underpin liposarcoma and Ewing's sarcoma, respectively. The translocated PrLDs alter the expression profiles of these proteins and promote their phase separation and aggreg...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Protein Structure and Folding Source Type: research
Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease–linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between excitotoxicity, RBP function, and disease have not been explored. Here, using primary cortical and motor neurons, we found that excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by excitotoxicity included TAR DNA&...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Molecular Bases of Disease Source Type: research
Abstract The RNaseA superfamily member Angiogenin (ANG) is a secreted protein involved in neovascularization, cell proliferation and stress response. Dysregulation of ANG expression is found in many cancers with poor prognosis and mutations in ANG are associated with neurodegenerative diseases. While the uptake and nuclear translocation of ANG is relatively well characterised, little is known about how it reaches the plasma membrane and its mode of secretion. We generated SH-SY5Y neuroblastoma cell lines constitutively expressing wild type (WT) Hemagglutinin (HA) epitope tagged mouse Ang1 (mAng1), and two amyotrop...
Source: Experimental Cell Research - Category: Cytology Authors: Tags: Exp Cell Res Source Type: research
ConclusionsIn the Hungarian ALS population, the observed frequency ofANG mutations was 2.9%, which is higher than previously reported for sporadic cohorts. The evidence from computational and functional analyses support the deleterious effect of the novel R33W variant detected in this study.
Source: Brain and Behavior - Category: Neurology Authors: Tags: ORIGINAL RESEARCH Source Type: research
Conclusions: We demonstrated in the SOD1G93A model of ALS that increased levels of several cytokines were associated with a shorter lifespan. However, their role as prognostic biomarkers is unclear as their expression was very variable depending on both the disease stage and the subject. Nevertheless, cytokines may be potential therapeutic targets. Introduction Amyotrophic Lateral Sclerosis (ALS) is one of the most common rare diseases of unknown origin that leads to progressive motor neuron degeneration and muscle denervation (1). In particular, it has been described that either distal axonopathy or neuromuscular ju...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Conclusions Stroke comprises ischemic stroke and ICH. The immuno-inflammatory process is involved in neural plasticity following events such as a hemorrhage or ischemic stroke. After ischemia, astrocytes, microglia, and MDMs play important roles during rehabilitation with the modulation of cytokines or chemokines, such as TNF-α and IL-1. Moreover, MiRNAs are also important posttranscriptional regulators in these glial mitochondrial responses to cerebral ischemia. ICH involves processes similar and different to those seen in ischemia, including neuronal injury, astrocytic and microglial/macrophage activation, and neu...
Source: Frontiers in Psychiatry - Category: Psychiatry Source Type: research
Publication date: Available online 29 November 2018Source: Mutation Research/Fundamental and Molecular Mechanisms of MutagenesisAuthor(s): Aditya K. Padhi, James GomesAbstractMissense mutations in certain genes of the Ribonuclease (RNASE) superfamily cause amyotrophic lateral sclerosis (ALS) through loss of either ribonucleolytic or nuclear translocation or both of these activities. While rare ANG/RNASE5 variants have been previously shown to be ALS causative, it is not yet known if any of the reported rare RNASE4 variants can also trigger ALS. The study aims to understand whether rare variants of RNASE4 can manifest ALS t...
Source: Mutation Research Fundamental and Molecular Mechanisms of Mutagenesis - Category: Cytology Source Type: research
ski A Abstract Neurodegeneration (NDG) is linked with the progressive loss of neural function with intellectual and/or motor impairment. Several diseases affecting older individuals, including Alzheimer's disease, Amyotrophic Lateral Sclerosis, Huntington's disease, Parkinson's disease, stroke, Multiple Sclerosis and many others, are the most relevant disorders associated with NDG. Since other pathologies such as refractory epilepsy, brain infections, or hereditary diseases such as "neurodegeneration with brain iron accumulation", also lead to chronic brain inflammation with loss of neural cells, NDG can...
Source: Epilepsy Curr - Category: Neurology Authors: Tags: Curr Neuropharmacol Source Type: research
Publication date: 24 July 2018Source: Cell Reports, Volume 24, Issue 4Author(s): Eva-Maria Hock, Zuzanna Maniecka, Marian Hruska-Plochan, Stefan Reber, Florent Laferrière, Sonu Sahadevan M.K., Helena Ederle, Lauren Gittings, Lucas Pelkmans, Luc Dupuis, Tammaryn Lashley, Marc-David Ruepp, Dorothee Dormann, Magdalini PolymenidouSummaryThe primarily nuclear RNA-binding protein FUS (fused in sarcoma) forms pathological cytoplasmic inclusions in a subset of early-onset amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. In response to cellular stress, FUS is recruited to cytoplasmic stress gra...
Source: Cell Reports - Category: Cytology Source Type: research
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