Overview of Glutamatergic Dysregulation in Central Pathologies

Miladinovic, Tanya; Nashed, Mina G.; Singh, Gurmit

doi:10.3390/biom5043112

Cited by 99 publications

(88 citation statements)

References 214 publications

(245 reference statements)

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“…؉/؊ /GLT1-cKO mice Nucleocytoplasmic transport has a crucial role in cell viability, and the loss of nucleoporins has been reported to impair nuclear import and export (Roth et al, 2003;Pemberton and Paschal, 2005;Bano et al, 2010;Nishimura et al, 2010;Makise et al, 2012;Yamashita et al, 2017a). Because GLAST ϩ/Ϫ /GLT1-cKO mice showed the reduction of Nup153 in motor neurons, we examined the changes in the subcellular localization of proteins involved in nucleocytoplasmic trafficking.…”

Section: Effects Of Short-term Treatment With the Nuclear Export Inhimentioning

confidence: 99%

Calpain-Dependent Degradation of Nucleoporins Contributes to Motor Neuron Death in a Mouse Model of Chronic Excitotoxicity

et al. 2017

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Glutamate-mediated excitotoxicity induces neuronal death by altering various intracellular signaling pathways and is implicated as a common pathogenic pathway in many neurodegenerative diseases. In the case of motor neuron disease, there is significant evidence to suggest that the overactivation of AMPA receptors due to deficiencies in the expression and function of glial glutamate transporters GLT1 and GLAST plays an important role in the mechanisms of neuronal death. However, a causal role for glial glutamate transporter dysfunction in motor neuron death remains unknown. Here, we developed a new animal model of excitotoxicity by conditionally deleting astroglial glutamate transporters GLT1 and GLAST in the spinal cords of mice (GLAST(+/-)/GLT1-cKO). GLAST(+/-)/GLT1-cKO mice (both sexes) exhibited nuclear irregularity and calpain-mediated degradation of nuclear pore complexes (NPCs), which are responsible for nucleocytoplasmic transport. These abnormalities were associated with progressive motor neuron loss, severe paralysis, and shortened lifespan. The nuclear export inhibitor KPT-350 slowed but did not prevent motor neuron death, whereas long-term treatment of the AMPA receptor antagonist perampanel and the calpain inhibitor SNJ-1945 had more persistent beneficial effects. Thus, NPC degradation contributes to AMPA receptor-mediated excitotoxic motor neuronal death, and preventing NPC degradation has robust protective effects. Normalization of NPC function could be a novel therapeutic strategy for neurodegenerative disorders in which AMPA receptor-mediated excitotoxicity is a contributory factor.SIGNIFICANCE STATEMENT Despite glial glutamate transporter dysfunction leading to excitotoxicity has been documented in many neurological diseases, it remains unclear whether its dysfunction is a primary cause or secondary outcome of neuronal death at disease state. Here we show the combined loss of glial glutamate transporters GLT1 and GLAST in spinal cord caused motor neuronal death and hindlimb paralysis. Further, our novel mutant exhibits the nuclear irregularities and calpain-mediated progressive nuclear pore complex degradation. Our study reveals that glial glutamate transporter dysfunction is sufficient to cause motor neuronal death in vivo. Glutamate-mediated excitotoxicity induces neuronal death by altering various intracellular signaling pathways and is implicated as a common pathogenic pathway in many neurodegenerative diseases. In the case of motor neuron disease, there is significant evidence to suggest that the overactivation of AMPA receptors due to deficiencies in the expression and function of glial glutamate transporters GLT1 and GLAST plays an important role in the mechanisms of neuronal death. However, a causal role for glial glutamate transporter dysfunction in motor neuron death remains unknown. Here, we developed a new animal model of excitotoxicity by conditionally deleting astroglial glutamate transporters GLT1 and GLAST in the spinal cords of mice (GLAST ϩ/Ϫ /GLT1-cKO). GLAST ϩ/Ϫ /G...

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Section: Effects Of Short-term Treatment With the Nuclear Export Inhimentioning

confidence: 99%

Calpain-Dependent Degradation of Nucleoporins Contributes to Motor Neuron Death in a Mouse Model of Chronic Excitotoxicity

et al. 2017

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“…Glutamate (Glu) and glutamine (Gln) are relatively abundant amino acids in the brain that are critical for neuronal function . The Glu–Gln cycle controls the supply of the neurotransmitter Glu by synaptic release of Glu or γ‐aminobutyric acid (GABA), which is taken up by astrocytes to release Gln that is used in the re‐synthesis of Glu or GABA.…”

Section: Introductionmentioning

confidence: 99%

Regional distributions of brain glutamate and glutamine in normal subjects

2016

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Glutamate (Glu) and glutamine (Gln) play an important role in neuronal regulation and are of value as MRS-observable diagnostic biomarkers. In this study the relative concentrations of these metabolites have been measured in multiple regions in the normal brain using a short-TE whole-brain MRSI measurement at 3T combined with a modified data analysis approach that used spatial averaging to obtain high-SNR spectra from atlas-registered anatomic regions or interest. By spectral fitting of high-SNR spectra this approach yielded reliable measurements across a wide volume of the brain. Spectral averaging also demonstrated increased SNR and improved fitting accuracy for the sum of Glu and Gln (Glx) compared to individual voxel fitting. Results in 26 healthy controls showed relatively constant Glu/Cr and Gln/Cr throughout the cerebrum, although with increased values in the anterior cingulum and paracentral lobule, and increased Gln/Cr in the superior motor area. The deep gray-matter regions of thalamus, putamen, and pallidum show lower Glu/Cr compared to cortical white-matter regions. Lobar measurements demonstrated reduced Glu/Cr and Gln/Cr in the cerebellum as compared to the cerebrum, where white-matter regions show significantly lower Glu/Cr and Gln/Cr as compared to gray-matter regions across multiple brain lobes. Regression analysis showed no significant effect of gender on Glu/Cr and Gln/Cr measurement, however, Glx/Cr ratio was found to be significantly negatively correlated to age in some lobar brain regions. In summary, this methodology provides the spectral quality necessary for reliable separation of Glu, and Gln at 3T from a single MRSI acquisition enabling generation of regional distributions of metabolites over a large volume of the brain, including cortical regions.

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“…Glutamate excess in the brain is associated with glutamate excitotoxicity, a cascade of events that eventually leads to oxidative stress, toxicity, and cell death. 10,11 Glutamine excess leads to insufficient osmoregulation and subsequent cerebral edema. 6,12 Glutamate and glutamine concentrations are therefore strictly regulated.…”

Section: Introductionmentioning

confidence: 99%

Inborn errors of enzymes in glutamate metabolism

Rumping

Vringer

Houwen

et al. 2019

J of Inher Metab Disea

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Glutamate is involved in a variety of metabolic pathways. We reviewed the literature on genetic defects of enzymes that directly metabolise glutamate, leading to inborn errors of glutamate metabolism. Seventeen genetic defects of glutamate metabolising enzymes have been reported, of which three were only recently identified. These 17 defects affect the inter‐conversion of glutamine and glutamate, amino acid metabolism, ammonia detoxification, and glutathione metabolism. We provide an overview of the clinical and biochemical phenotypes of these rare defects in an effort to ease their recognition. By categorising these by biochemical pathway, we aim to create insight into the contributing role of deviant glutamate and glutamine levels to the pathophysiology. For those disorders involving the inter‐conversion of glutamine and glutamate, these deviant levels are postulated to play a pivotal pathophysiologic role. For the other IEM however—with the exception of urea cycle defects—abnormal glutamate and glutamine concentrations were rarely reported. To create insight into the clinical consequences of disturbed glutamate metabolism—rather than individual glutamate and glutamine levels—the prevalence of phenotypic abnormalities within the 17 IEM was compared to their prevalence within all Mendelian disorders and subsequently all disorders with metabolic abnormalities notated in the Human Phenotype Ontology (HPO) database. For this, a hierarchical database of all phenotypic abnormalities of the 17 defects in glutamate metabolism based on HPO was created. A neurologic phenotypic spectrum of developmental delay, ataxia, seizures, and hypotonia are common in the inborn errors of enzymes in glutamate metabolism. Additionally, ophthalmologic and skin abnormalities are often present, suggesting that disturbed glutamate homeostasis affects tissues of ectodermal origin: brain, eye, and skin. Reporting glutamate and glutamine concentrations in patients with inborn errors of glutamate metabolism would provide additional insight into the pathophysiology.

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Overview of Glutamatergic Dysregulation in Central Pathologies

Cited by 99 publications

References 214 publications

Calpain-Dependent Degradation of Nucleoporins Contributes to Motor Neuron Death in a Mouse Model of Chronic Excitotoxicity

Calpain-Dependent Degradation of Nucleoporins Contributes to Motor Neuron Death in a Mouse Model of Chronic Excitotoxicity

Regional distributions of brain glutamate and glutamine in normal subjects

Inborn errors of enzymes in glutamate metabolism

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