TCA Concentrations in Neuromyelitis Optica Patients (part - II)
Ontology highlight
ABSTRACT:
ORGANISM(S): Human Homo Sapiens
TISSUE(S): Astrocyte Cells
DISEASE(S): Inflammation
SUBMITTER: 
Charles Howe
PROVIDER: ST001036 | MetabolomicsWorkbench | Mon Aug 13 00:00:00 BST 2018
REPOSITORIES: MetabolomicsWorkbench
Dataset's files
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Project description:Patients with an inflammatory disease of the central nervous system known as neuromyelitis optica (NMO) experience increased levels of depression. These patients have an antibody that recognizes a type of cell in the brain called astrocytes – binding of this antibody to astrocytes triggers a stress response in the cell that results in the development of brain lesions that cause disability and cognitive disturbances. We recently observed a change in the level of glutamate in a part of the brain involved in depression in patients with NMO. Glutamate is a chemical that is used in the brain for communication between neurons – reduced levels of glutamate are thought to trigger depression by reducing neuronal activity in specific circuits. Based on this observation and the known role of astrocytes in maintaining glutamate levels in the brain, we hypothesize that the NMO antibody disturbs metabolic activity in astrocytes and thereby reduces glutamate and triggers depression. We intend to trace the metabolic response induced in astrocytes by the NMO antibody using TCA isotopomers. It is our hope that we will not only learn something about the mechanisms of astrocyte dysregulation in neuromyelitis optica, but that we will learn something about the mechanisms of depression in general that may lead to new therapies for this disease.
2018-08-13 | ST001035 | MetabolomicsWorkbench
Project description:The creatine-phosphocreatine cycle serves as a crucial temporary energy buffering system in the brain, regulated by brain creatine kinase (CKB). CKB, responsible for reversible phosphorylation of creatine, plays a pivotal role in maintaining ATP levels. Alzheimer's disease (AD) has been linked to increased CKB oxidation and loss of its functions, although specific pathological processes and affected cell types remain unclear.
In our study, cerebral cortex samples from AD, dementia with Lewy bodies (DLB), and age-matched controls were analyzed using antibody-based methods to quantify CKB levels and assess alterations associated with disease processes. Two independently validated antibodies exclusively labeled astrocytes in the human cerebral cortex. Immunofluorescence and Western blot analyses demonstrated a loss of CKB immunoreactivity correlated with increased plaque load, severity of tau pathology, and Lewy body pathology.
Combining antibody-based and mass spectrometry (MS) approaches, we explored CKB availability in AD and DLB. Transcriptomics and targeted MS revealed unaltered total CKB levels. Reduced antibody binding levels, confirmed by Western blot under denatured conditions, suggested post-translational modifications that affect antibody binding. This aligns with altered efficiency at proteolytic cleavage sites indicated in the targeted MS experiment.
These findings highlight that post-translational modifications extend to astrocytes, affecting their functions. CKB and the creatine-phosphocreatine cycle play crucial roles in energy buffering, securing constant ATP availability. Reduced ATP in astrocytes can disrupt ATP-dependent processes, such as the glutamate-glutamine cycle. Post-translational modifications in CKB and astrocyte dysfunction may disturb homeostasis, driving excitotoxicity in the AD brain. CKB and its activity emerge as potential biomarkers for monitoring early-stage energy deficits in AD.
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Project description:Familial hemiplegic migraine is an episodic neurological disorder characterized by transient sensory and motor symptoms and signs. Mutations of the ion pump alpha2-Na/K ATPase represent a key genetic cause of familial hemiplegic migraine, but the mechanisms by which alpha2-Na/K ATPase mutations lead to the migraine phenotype remain incompletely understood. Here, we unexpectedly find that mice in which alpha2-Na/K ATPase is conditionally deleted in astrocytes display episodic transient motor paralysis. Functional neuroimaging reveals that conditional knockout of alpha2-Na/K ATPase triggers spontaneous cortical spreading depression events that are associated with low voltage activity events upon EEG monitoring, which in turn correlate with transient motor impairment in these mice. Transcriptomic and metabolomic analyses show that loss of alpha2-Na/K ATPase alters metabolic gene expression in astrocytes in vivo with consequent elevation of serine and glycine in the brain. Strikingly, feeding alpha2-Na/K ATPase knockout mice a serine- and glycine-free diet reverses the phenotype of transient motor impairment. Together, our findings define a novel metabolic mechanism regulated by astrocytic alpha2-Na/K ATPase that triggers episodic transient motor paralysis in mice, laying the foundation for potential new treatment strategies for patients with familial hemiplegic migraine.
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Project description:Molecular pathways mediating systemic inflammation entering the brain parenchyma to induce sepsis-associated encephalopathy (SAE) remain elusive. Here, we report that in mice during the first 6 hours of peripheral lipopolysaccharide (LPS)-evoked systemic inflammation (6 hpi), the plasma level of adenosine quickly increased and enhanced the tone of central extracellular adenosine which then provoked neuroinflammation by triggering early astrocyte reactivity. Specific ablation of astrocytic A1 adenosine receptors (A1ARs) prevented this early reactivity and reduced the levels of inflammatory factors (e.g., CCL2, CCL5, and CXCL1) in astrocytes, thereby alleviating microglial reaction, ameliorating blood-brain barrier disruption, peripheral immune cell infiltration, neuronal dysfunction, and depression-like behaviour in the mice. Chemogenetic stimulation of Gi signaling in A1AR-deficent astrocytes at 2 and 4 hpi of LPS injection could restore neuroinflammation and depression-like behaviour, highlighting astrocytes rather than microglia as early drivers of neuroinflammation. Our results identify early astrocyte reactivity towards peripheral and central levels of adenosine as a novel pathway driving SAE and highlight the potential of targeting A1ARs for therapeutic intervention.
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Project description:Cloutier2009 - Brain Energy Metabolism
This model was taken from the
CellML
repository
and
automatically converted to SBML. Following the
submission the parameters are manually encoded and annotated as
spices and global quantities by BioModels curators.
The
original model was:
Cloutier M, Bolger FB, Lowry JP, Wellstead P. (2009) -
version=1.0
The
original CellML model was created by:
Catherine
Lloyd
c.lloyd@auckland.ac.nz
The
University of Auckland
This model is described in the article:
An integrative dynamic model
of brain energy metabolism using in vivo neurochemical
measurements.
Cloutier M, Bolger FB, Lowry JP,
Wellstead P.
J Comput Neurosci 2009 Dec; 27(3):
391-414
Abstract:
An integrative, systems approach to the modelling of brain
energy metabolism is presented. Mechanisms such as glutamate
cycling between neurons and astrocytes and glycogen storage in
astrocytes have been implemented. A unique feature of the model
is its calibration using in vivo data of brain glucose and
lactate from freely moving rats under various stimuli. The
model has been used to perform simulated perturbation
experiments that show that glycogen breakdown in astrocytes is
significantly activated during sensory (tail pinch)
stimulation. This mechanism provides an additional input of
energy substrate during high consumption phases. By way of
validation, data from the perfusion of 50 microM propranolol in
the rat brain was compared with the model outputs. Propranolol
affects the glucose dynamics during stimulation, and this was
accurately reproduced in the model by a reduction in the
glycogen breakdown in astrocytes. The model's predictive
capacity was verified by using data from a sensory stimulation
(restraint) that was not used for model calibration. Finally, a
sensitivity analysis was conducted on the model parameters,
this showed that the control of energy metabolism and transport
processes are critical in the metabolic behaviour of cerebral
tissue.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000554.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000554 | BioModels
Project description:Psychiatric disorders, especially major depressive disorder, are prominent cause of disability worldwide, and in dire need of better diagnostic and therapeutic tools. In order to identify the cellular mechanisms underlying major depressive disorder we sought to understand the role of astrocytes, the most numerous subtype of glia, in this disease utilizing the TRAP gene expression analysis and chronic social defeat mouse model of depression. TRAP translational profiling is a method that allows investigators to genetically characterize specific cell types in complex tissues such as mouse brain. Using this technique we obtained RNA-Seq data from actively translating transcripts present in astrocytes. We generated the molecular profile of astrocytes from multiple brain regions affected by stress-induced depression, the prefrontal cortex, hippocampus, accumbens nucleus and caudate putamen of adult Aldh1l1-EGFP/Rpl10a (JD130) mice after chronic social defeat stress paradigm. The results of this study will further our understanding of depression pathophysiology and will provide possible targets for novel or supplementary therapies.
2019-12-02 | GSE139684 | GEO
Project description:Downregulation of expression and activity levels of the astroglial glutamate transporter EAAT2 is thought to be implicated in motor neuron excitotoxicity in amyotrophic lateral sclerosis (ALS). We previously reported that EAAT2 is cleaved by caspase-3 at the cytosolic C-terminus domain, impairing the transport activity and generating a proteolytic fragment found to be SUMO1 conjugated (CTE-SUMO1). We show here that this fragment accumulates in the nucleus of spinal cord astrocytes in vivo throughout the disease stages of the SOD1-G93A mouse model of ALS. In vitro expression in spinal cord astrocytes of the C-terminus peptide of EAAT2 (CTE), which was artificially fused to SUMO1 (CTE-SUMO1fus) to mimic the endogenous SUMOylation reaction, recapitulates the nuclear accumulation of the fragment seen in vivo and causes caspase-3 activation and axonal growth impairment in motor neuron-derived NSC-34 cells and primary motor neurons co-cultured with CTE-SUMO1fus-expressing spinal cord astrocytes. This indicates that CTE-SUMO1fus could trigger non-cell autonomous mechanisms of neurodegeneration. Prolonged nuclear accumulation of CTE-SUMO1fus in astrocytes leads to their degeneration, although the time frame of the cell-autonomous toxicity is longer than the one for the indirect toxic effect on motor neurons. As more evidence on the implication of SUMO substrates in neurodegenerative diseases emerges, our observations strongly suggest that the nuclear accumulation in spinal cord astrocytes of a SUMOylated proteolytic fragment of the astroglial glutamate transporter EAAT2 could take part to the pathogenesis of ALS and suggest a novel, unconventional role for EAAT2 in motor neuron degeneration in ALS. Comparison is made between the toxic fragment (SUMO) and the same fragment without lysines that can be sumo-ylated (CTE). Four replicates have been performed for each sample group.
2011-07-19 | E-GEOD-26070 | biostudies-arrayexpress
Project description:Mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are yet unclear. Specific deletion of the ER-component membralin in astrocytes manifested postnatal motor defects and lethality in mice, causing the accumulation of extracellular glutamate through reducing the glutamate transporter EAAT2. Restoring EAAT2 levels in membralin KO astrocytes limited astrocyte-dependent excitotoxicity in motor neurons. Transcriptomic profiles from mouse astrocytic membralin KO motor cortex indicateed significant perturbation in KEGG pathway components related to ALS, including downregulation of Eaat2 and upregulation of Tnfrsf1a. Changes in gene expression with membralin deletion also overlapped with mouse ALS models and reactive astrocytes. Our results shown that activation of TNF receptor (TNFR1)-NFkB pathway known to suppress Eaat2 transcription was upregulated with membralin deletion. Further, reduced membralin and EAAT2 levels correlated with disease progression in spinal cord from SOD1-mutant mouse models, and reductions in membralin/EAAT2 were observed in human ALS spinal cord. Importantly, overexpression of membralin in SOD1G93A astrocytes decreased TNFR1 levels and increased EAAT2 expression, and improved motor neuron survival. Importantly, upregulation of membralin in SOD1G93A mice significantly prolonged mouse survival. Together, our study provides a mechanism for ALS pathogenesis where membralin limits glutamatergic neurotoxicity, suggesting that modulating membralin has potential in ALS therapy
2019-05-07 | GSE130763 | GEO
Project description:Glycogen storage, conversion and utilization in astrocytes play important roles in brain energy metabolism. The conversion of glycogen to lactate through glycolysis occurs through the coordinated activities of various enzymes, and inhibition of this process can impair different brain processes including formation of long-lasting memories. To replenish depleted glycogen stores, astrocytes undergo glycogen synthesis, a cellular process that has been shown to require transcription and translation during specific stimulation paradigms. However, the detailed nuclear signaling mechanisms and transcriptional regulation during glycogen synthesis in astrocytes remain to be explored. In this report, we study the molecular details of vasoactive intestinal peptide (VIP)-induced glycogen synthesis in astrocytes. VIP is a potent neuropeptide that triggers glycogenolysis followed by glycogen synthesis in astrocytes. We show evidence that VIP-induced glycogen synthesis requires CREB-mediated transcription that is Protein Kinase C and calcium-dependent but is independent of Protein Kinase A. In parallel to CREB activation, we demonstrate that VIP also triggers nuclear accumulation of the CREB coactivator CRTC2 only in astrocytic nuclei that also requires Protein Kinase C activity. Transcriptome profiles of VIP-induced astrocytes identified robust CREB-dependent transcription of glycogenic genes including the upregulation of Ppp1r3c along with robust repression of Phkg1, the catalytic subunit of phosphorylase kinase. Overall, our data demonstrates the importance of CREB-mediated transcription in astrocytes during stimulus-driven glycogenesis.
2024-04-30 | GSE243500 | GEO