Abnormal glutamate metabolism in amyotrophic lateral sclerosis

Plaitakis, Andreas; Caroscio, James T.

doi:10.1002/ana.410220503

Cited by 282 publications

(101 citation statements)

References 22 publications

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“…Possession of AMPA /kainate receptors gating channels with direct Ca 2ϩ permeability might result in similar excess free-radical production in motor neurons during AMPA /kainate receptor activation. If so, free-radical mediated oxidative injury to motor neurons could be an injury mechanism common to excitotoxic models of ALS (Plaitakis and Caroscio, 1987;Rothstein et al, 1990Rothstein et al, , 1992 as well as to recently described familial forms of the disease linked to mutations in the free-radical metabolizing enzyme superoxide dismutase (Rosen et al, 1993).…”

Section: Excitotoxic Vulnerability Of Cultured Motor Neuronsmentioning

confidence: 99%

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Motor Neurons Are Selectively Vulnerable to AMPA/Kainate Receptor-Mediated InjuryIn Vitro

1996

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The nonphosphorylated neurofilament marker SMI-32 stains motor neurons in spinal cord slices and stains a subset of cultured spinal neurons neurons"], which have a morphology consistent with motor neurons identified in vitro: large cell body, long axon, and extensive dendritic arborization. They are found preferentially in ventral spinal cord cultures, providing further evidence that large SMI-32(ϩ) neurons are indeed motor neurons, and SMI-32 staining often colocalizes with established motor neuron markers (including acetylcholine, calcitonin gene-related peptide, and peripherin). Additionally, choline acetyltransferase activity (a frequently used index of the motor neuron population) and peripherin(ϩ) neurons share with large SMI-32(ϩ) neurons an unusual vulnerability to AMPA /kainate receptor-mediated injury. Kainateinduced loss of these motor neuron markers is Ca 2ϩ -dependent, which supports a critical role of Ca 2ϩ ions in this injury. Raising extracellular Ca 2ϩ exacerbates injury, whereas removal of extracellular Ca 2ϩ is protective. A basis for this vulnerability is provided by the observation that most peripherin(ϩ) neurons, like large SMI-32(ϩ) neurons, are subject to kainate-stimulated Co 2ϩ uptake, a histochemical stain that identifies neurons possessing Ca 2ϩ -permeable AMPA /kainate receptor-gated channels. Finally, of possibly greater relevance to the slow motor neuronal degeneration in diseases, both large SMI-32(ϩ) neurons and peripherin(ϩ) neurons are selectively damaged by prolonged (24 hr) low-level exposures to kainate (10 M) or to the glutamate reuptake blocker L-transpyrrolidine-2,4-dicarboxylic acid (100 M). During these lowlevel kainate exposures, large SMI-32(ϩ) neurons showed higher intracellular Ca 2ϩ concentrations than most spinal neurons, suggesting that Ca 2ϩ ions are also important in this more slowly evolving injury.

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Section: Excitotoxic Vulnerability Of Cultured Motor Neuronsmentioning

confidence: 99%

“…Although of unknown cause, findings of abnormalities in the uptake (Rothstein et al, 1992) or metabolism (Plaitakis and Caroscio, 1987;Hugon et al, 1989a;Rothstein et al, 1990) of glutamate and related excitatory amino acids suggest that excitotoxic injury may be a contributory factor.…”

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confidence: 99%

Motor Neurons Are Selectively Vulnerable to AMPA/Kainate Receptor-Mediated InjuryIn Vitro

1996

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“…Glutamate accumulation-mediated neurotoxicity is known to play a crucial role in traumatic and ischemic brain injuries, as well as in neurodegenerative diseases including ALS (Culcasi et al, 1994;Fiszman et al, 2010;Grosskreutz et al, 2010;Lafon-Cazal et al, 1993;Perry et al, 1987;Plaitakis and Caroscio, 1987). The elevation of glutamate concentration causes neurotoxicity through overactivation of ionotropic glutamate receptors (Arundine and Tymianski, 2004;Hanson et al, 2010;Hardingham et al, 2002;Lee et al, 1999;Rothstein et al, 1990;Sarraf-Yazdi et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

Liao

Cui

et al. 2012

Journal of Cell Science

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SummaryThe dysfunction of TAR DNA-binding protein-43 (TDP-43) is implicated in neurodegenerative diseases. However, the function of TDP-43 is not fully elucidated. Here we show that the protein level of endogenous TDP-43 in the nucleus is increased in mouse cortical neurons in the early stages, but return to basal level in the later stages after glutamate accumulation-induced injury. The elevation of TDP-43 results from a downregulation of phosphatase and tensin homolog (PTEN). We further demonstrate that activation of NR2A-containing NMDA receptors (NR2ARs) leads to PTEN downregulation and subsequent reduction of PTEN import from the cytoplasm to the nucleus after glutamate accumulation. The decrease of PTEN in the nucleus contributes to its reduced association with TDP-43, and thereby mediates the elevation of nuclear TDP-43. We provide evidence that the elevation of nuclear TDP-43, mediated by NR2AR activation and PTEN downregulation, confers protection against cortical neuronal death in the late stages after glutamate accumulation. Thus, this study reveals a NR2AR-PTEN-TDP-43 signaling pathway by which nuclear TDP-43 promotes neuronal survival. These results suggest that upregulation of nuclear TDP-43 represents a self-protection mechanism to delay neurodegeneration in the early stages after glutamate accumulation and that prolonging the upregulation process of nuclear TDP-43 might have therapeutic significance.

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“…64 This study, aimed at comparing amino acid levels in 12 ALS patients with those of 12 control patients, matched for age, sex, and severity of disability (affected by diverse paralytic disorders), reports that glutamate concentrations are unchanged in cerebrospinal fluid (CSF) and not significantly increased in serum and urine, suggesting that there is no glutamate-associated specific signature in ALS patients. However, this was challenged a decade later, when plasma 65 and CSF 66 glutamate levels of 18 to 22 ALS patients were shown to be doubled compared to healthy controls and other neurological disorders patients. From then, the controversy continued, as some groups confirmed glutamate increases in plasma 67 or CSF 68 while others did not.…”

Section: Glutamate and Als: History And Controversiesmentioning

confidence: 99%

Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

Verche¹,

Ikiz²,

Jacquier³

et al. 2010

JRLCR

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Abstract:The cause of the fatal motor neuron disease, amyotrophic lateral sclerosis (ALS), remains largely unknown. Most cases of ALS are sporadic and, for ∼20% of familial ALS patients, mutations in the superoxide dismutase-1 (SOD1) gene have been identified. Transgenic rodents overexpressing mutant SOD1 emulate the disease and constitute the best ALS animal model so far. Several lines of evidence suggest that ALS is a multifactorial condition. In this review, we discuss the question of the involvement of the glutamate pathways in ALS-induced motor neuron death. As such, we review the data implicating glutamate metabolism alterations, glutamatergic environmental toxins, glutamate transporter/receptor defects, and Ca 2+ -mediated glutamate toxicity in the etiopathogenesis of ALS. Given the published data, we contend that glutamate-induced neurotoxicity more likely precipitates motor neuron degeneration rather than being the initiating factor of ALS. Furthermore, we propose that glutamate-induced neurotoxicity participates in the ALS deadly molecular cascade only as an executioner to put an end to a series of molecular perturbations that have irreversibly compromised motor neuron function. This could provide an explanation for the modest effect of therapeutic strategies targeting the glutamatergic system, including the only currently FDA-approved ALS treatment, riluzole. As in diseased motor neurons, overwhelming Ca 2+ overload may be the converging point for glutamate, endoplasmic reticulum stress, and mitochondrial dysfunctional pathways, and only therapies targeting these simultaneously or targeting the earliest alterations initiating this deleterious cascade may have a real impact on halting ALS progression.

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Abnormal glutamate metabolism in amyotrophic lateral sclerosis

Cited by 282 publications

References 22 publications

Motor Neurons Are Selectively Vulnerable to AMPA/Kainate Receptor-Mediated InjuryIn Vitro

Motor Neurons Are Selectively Vulnerable to AMPA/Kainate Receptor-Mediated InjuryIn Vitro

Regulation of nuclear TDP-43 by NR2A-containing NMDA receptors and PTEN

Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

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