1,721,069 research outputs found
The Physio-Pathological Role of Group I Metabotropic Glutamate Receptors Expressed by Microglia in Health and Disease with a Focus on Amyotrophic Lateral Sclerosis
No full textMicroglia cells are the resident immune cells of the central nervous system. They act as the first-line immune guardians of nervous tissue and central drivers of neuroinflammation. Any homeostatic alteration that can compromise neuron and tissue integrity could activate microglia. Once activated, microglia exhibit highly diverse phenotypes and functions related to either beneficial or harmful consequences. Microglia activation is associated with the release of protective or deleterious cytokines, chemokines, and growth factors that can in turn determine defensive or pathological outcomes. This scenario is complicated by the pathology-related specific phenotypes that microglia can assume, thus leading to the so-called disease-associated microglia phenotypes. Microglia express several receptors that regulate the balance between pro- and anti-inflammatory features, sometimes exerting opposite actions on microglial functions according to specific conditions. In this context, group I metabotropic glutamate receptors (mGluRs) are molecular structures that may contribute to the modulation of the reactive phenotype of microglia cells, and this is worthy of exploration. Here, we summarize the role of group I mGluRs in shaping microglia cells’ phenotype in specific physio-pathological conditions, including some neurodegenerative disorders. A significant section of the review is specifically focused on amyotrophic lateral sclerosis (ALS) since it represents an entirely unexplored topic of research in the field
A multistationary loop model of ALS unveils critical molecular interactions involving mitochondria and glucose metabolism
No full textAmyotrophic lateral sclerosis (ALS) is a poor-prognosis disease with puzzling pathogenesis and inconclusive treatments. We develop a mathematical model of ALS based on a system of interactive feedback loops, focusing on the mutant SOD1G93A mouse. Misfolded mutant SOD1 aggregates in motor neuron (MN) mitochondria and triggers a first loop characterized by oxidative phosphorylation impairment, AMP kinase over-activation, 6-phosphofructo-2-kinase (PFK3) rise, glucose metabolism shift from pentose phosphate pathway (PPP) to glycolysis, cell redox unbalance, and further worsening of mitochondrial dysfunction. Oxidative stress then triggers a second loop, involving the excitotoxic glutamatergic cascade, with cytosolic Ca2+ overload, increase of PFK3 expression, and further metabolic shift from PPP to glycolysis. Finally, cytosolic Ca2+ rise is also detrimental to mitochondria and oxidative phosphorylation, thus closing a third loop. These three loops are overlapped and positive (including an even number of inhibitory steps), hence they form a candidate multistationary (bistable) system. To describe the system dynamics, we model the interactions among the functional agents with differential equations. The system turns out to admit two stable equilibria: the healthy state, with high oxidative phosphorylation and preferential PPP, and the pathological state, with AMP kinase activation, PFK3 over expression, oxidative stress, excitotoxicity and MN degeneration. We demonstrate that the loop system is monotone: all functional agents consistently act toward the healthy or pathological condition, depending on low or high mutant SOD1 input. We also highlight that molecular interactions involving PFK3 are crucial, as their deletion disrupts the system’s bistability leading to a single healthy equilibrium point. Hence, our mathematical model unveils that promising ALS management strategies should be targeted to mechanisms that keep low PFK3 expression and activity within MNs.Team Tamas Keviczk
The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity
No full textIn the last two decades, there has been increasing evidence supporting non-neuronal cells as active contributors to neurodegenerative disorders. Among glial cells, astrocytes play a pivotal role in driving amyotrophic lateral sclerosis (ALS) progression, leading the scientific community to focus on the “astrocytic signature” in ALS. Here, we summarized the main pathological mechanisms characterizing astrocyte contribution to MN damage and ALS progression, such as neuroinflammation, mitochondrial dysfunction, oxidative stress, energy metabolism impairment, miRNAs and extracellular vesicles contribution, autophagy dysfunction, protein misfolding, and altered neurotrophic factor release. Since glutamate excitotoxicity is one of the most relevant ALS features, we focused on the specific contribution of ALS astrocytes in this aspect, highlighting the known or potential molecular mechanisms by which astrocytes participate in increasing the extracellular glutamate level in ALS and, conversely, undergo the toxic effect of the excessive glutamate. In this scenario, astrocytes can behave as “producers” and “targets” of the high extracellular glutamate levels, going through changes that can affect themselves and, in turn, the neuronal and non-neuronal surrounding cells, thus actively impacting the ALS course. Moreover, this review aims to point out knowledge gaps that deserve further investigation
Effects of BND-11624 at ionotropic and metabotropic glutamatergic receptors regulating neurotransmitter release in the rat CNS
No full textKnocking-down mGluR1 and mGluR5 in the SOD1/G93A mouse model of amyotrophic lateral sclerosis ameliorates survival and disease progression
No full textAstrocyte contribution to the excessive glutamate release in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis
No full textGlutamate (Glu) excitotoxicity plays a major role in amyotrophic lateral sclerosis (ALS) and elevated extracellular Glu levels were found in patients and animal models of the disease. Reduced astrocyte uptake was suggested as the main cause for increased Glu availability. On the basis of our experiments, we postulated that abnormal neurotransmitter release represents another source for elevated Glu. Indeed, we found that neuronal Glu release from spinal cord synaptosomes is abnormally high in the spinal cord of pre-symptomatic and symptomatic SOD1G93A mice, a widely used experimental model of ALS, under resting conditions and upon exposure to different stimuli able to induce Glu exocytosis, including KCl depolarization, ionomycin, hypertonic sucrose or activation of Group I metabotropic Glu receptors. Also GABA and glycine induced Glu release in mouse spinal cord synaptosomes by activation of the respective transportes expressed at Glu-releasing terminals (heterotransporters) and also this effect was more elevated in SOD1G93A mice than in controls.
We report here the effect of GABA on Glu release from gliosomes, an astrocytic preparation obtained by tissue homogenization and Percoll® gradient purification, that represent viable particles originating from the astrocytes sorrounding the synapses. Interestingly, GABA induced Glu release by a heterotransporter-mediated mechanism also from gliosomes purified from the spinal cord of SOD1G93A mice and the effect of GABA was up regulated, leading to over release of Glu. The excessive release of Glu evoked by GABA was already present in the pre-symptomatic stage of the disease.
Our results indicate that abnormal Glu release from astrocytes is present in pre-symptomatic and symptomatic SOD1G93A mice. Thus, astrocytes may contribute to the increased concentration of Glu at glutamatergic synapses, to the activation of presynaptic and post-synaptic Glu receptors, and to excitotoxicity
Partial deletion of mGluR1 receptors prolongs life span and ameliorates motor skills and biochemical and cellular parameters in a mouse model of experimental ALS
No full textSytemic administration of nt-1640 improves survival and motor function in the SOD1/G93A mouse model of ALS.
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