Developmental Changes of N‐Acetyl‐L‐Aspartic Acid, N‐Acetyl‐α‐Aspartylglutamic Acid and β‐Citryl‐L‐Glutamic Acid in Different Brain Regions and Spinal Cords of Rat and Guinea Pig

Miyake, Masanobu; Kawaguchi, Yasuo

doi:10.1111/j.1471-4159.1981.tb04500.x

Cited by 57 publications

(27 citation statements)

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“…Additionally, Urenjak et al (1993) have found that the qualitative and quantitative differences between 'H-NMR spectra obtained from different purified populations of neural cells appears to be strongly correlated with the lineage of the cell type examined. In this respect, the higher levels of NAA found in less-differentiated PNETs and Miyake and Kakimoto (1981) and Bates et al (1989), the relative contribution of the neuronal and 0-2A lineages to this rise is unclear. Therefore, it is not possible to say whether the NAA levels observed in PNET cell lines are typical of dividing neuronal progenitors of the cerebellum.…”

Section: Observations)mentioning

confidence: 99%

Metabolic studies of human primitive neuroectodermal tumour cells by proton nuclear magnetic resonance spectroscopy

Florian

Pietsch²,

Noble³

et al. 1997

Br J Cancer

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Summary Well-characterized cell lines established from primitive neuroectodermal tumours (PNETs) were examined by proton nuclear magnetic resonance ('H-NMR) spectroscopy and chromatographic analysis of perchloric acid extracts, following amplification in cell culture. A characteristic 'H-NMR spectroscopic metabolite pattern was found for medulloblastoma cell lines, which clearly discriminates these cells from PNETs of other locations in the central nervous system (CNS), on the basis of their N-acetyl aspartate (NM) and aspartate expression. Medulloblastoma cell lines were heterogeneous in respect of their metabolite expression, possibly owing to the heterogeneity in their differentiation along lineages of the CNS. All PNET spectra displayed similar features, including decreased NAA and creatine peaks and increased signals from choline compounds (Cho) compared with normal cerebellum. The expression of NM by the medulloblastoma lines was in the opposite order to the extent of neuronal differentiation, which may indicate their origin from a progenitor cell with the phenotype of an oligodendrocyte-type-2 astrocyte cell.Keywords: human primitive neuroectodermal tumour; human medulloblastoma; proton nuclear magnetic resonance spectroscopy; metabolite; cell line Primitive neuroectodermal tumours (PNETs) are highly malignant [grade IV according to the World Health Organization classification of brain tumours by Kleihues et al (1993)] and among the most common tumours of childhood. They are most frequently located in the cerebellum (i.e. cerebellar medulloblastomas), but tumours that have a similar appearance and biological behaviour have been found in other locations in the central nervous system (CNS), such as the cerebrum, pineal region or spinal cord. The nature and cell of origin of these tumours, composed of primitive or undifferentiated neuroepithelial cells, is controversial. Questions have been raised as to whether their cell of origin is unique to the portion of the CNS in which the tumour arises, or whether there is a primitive or undifferentiated cell common to all portions of the CNS. Rorke et al (1985) have suggested that these tumours arise from a single primitive multipotential cell that has the capacity to differentiate into one or more types of neural cellssuch as astrocytes, oligodendrocytes, neurons, ganglion cells or melanocytes -and are therefore regarded as malignant counterparts of multipotential neural progenitor cells.Progress in understanding the cell biology of these tumours has been hampered by the lack of cultured cell lines, since relatively few continuous medulloblastoma lines have been established thus far (Friedman et al, 1985;Jacobsen et al, 1985). However, the recent establishment of five new human PNET cell lines from surgical specimens (Pietsch et al, 1994) Correspondence to: S Williams investigate the biology, phenotype, lineage and metabolism of PNETs in detail. In the present study, metabolite profiles of several of these PNET cell lines in culture, together with two establishe...

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Section: Observations)mentioning

confidence: 99%

Metabolic studies of human primitive neuroectodermal tumour cells by proton nuclear magnetic resonance spectroscopy

Florian

Pietsch²,

Noble³

et al. 1997

Br J Cancer

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“…BCG also was detected in kidneys and heart and to a much lower extent in intestine, spinal cord, and lung of newborn rats. The content of BCG in all organs decreased with age to the noticeable exception of testes, where its concentration increases during sexual maturation and remains constant in adulthood (8,9). BCG is present not only in the testes of mammals but also in those of amphibians and fishes.…”

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confidence: 97%

Molecular Identification of N-Acetylaspartylglutamate Synthase and β-Citrylglutamate Synthase

Collard

Stroobant

Lamosa

et al. 2010

Journal of Biological Chemistry

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The purpose of the present work was to determine the identity of the enzymes that synthesize N-acetylaspartylglutamate (NAAG), the most abundant dipeptide present in vertebrate central nervous system (CNS), and ␤-citrylglutamate, a structural analogue of NAAG present in testis and immature brain. Previous evidence suggests that NAAG is not synthesized on ribosomes but presumably is synthesized by a ligase. As attempts to detect this ligase in brain extracts failed, we searched the mammalian genomes for putative enzymes that could catalyze this type of reaction. Mammalian genomes were found to encode two putative ligases homologous to Escherichia coli RIMK, which ligates glutamates to the C terminus of ribosomal protein S6. One of them, named RIMKLA, is almost exclusively expressed in the CNS, whereas RIMKLB, which shares 65% sequence identity with RIMKLA, is expressed in CNS and testis. Both proteins were expressed in bacteria or HEK293T cells and purified. RIMKLA catalyzed the ATP-dependent synthesis of N-acetylaspartylglutamate from N-acetylaspartate and L-glutamate. RIMKLB catalyzed this reaction as well as the synthesis of ␤-citrylglutamate. The nature of the reaction products was confirmed by mass spectrometry and NMR. RIMKLA was shown to produce stoichiometric amounts of NAAG and ADP, in agreement with its belonging to the ATP-grasp family of ligases. The molecular identification of these two enzymes will facilitate progress in the understanding of the function of NAAG and ␤-citrylglutamate. N-Acetylaspartylglutamate (NAAG),3 the most abundant dipeptide in the CNS, is present in brain and in the spinal cord, most particularly in neurons of the anterior horn (1). NAAG can be released from neurons upon calcium depolarization (reviewed in Ref. 1) and is a substrate for two glial peptidases, glutamate carboxypeptidase-II (2) and, to a lower extent, glutamate carboxypeptidase-III (3), which are anchored to the plasma membrane with their catalytic site oriented toward the outside of the cell. NAAG long has been thought to be a neurotransmitter able to bind to the metabotropic glutamate receptors mGluR3 (4). Two recent reports suggest, however, that the effects of NAAG as a neurotransmitter are due to a 0.5% glutamate contamination present in commercial NAAG (5, 6). The function of NAAG is, therefore, presently unknown.␤-Citrylglutamate (BCG), which is structurally close to NAAG, is less well characterized. It was first identified in newborn rat brain, where its concentration reaches 0.5-1 mol/g at birth and then decreases with age (7). BCG also was detected in kidneys and heart and to a much lower extent in intestine, spinal cord, and lung of newborn rats. The content of BCG in all organs decreased with age to the noticeable exception of testes, where its concentration increases during sexual maturation and remains constant in adulthood (8,9). BCG is present not only in the testes of mammals but also in those of amphibians and fishes. There is evidence in germinal cells for a role in spermatogenesis (9). BCG rec...

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“…It is an accepted fact that NAA, which is present in the brain at concentrations 100-fold higher than those in non-nervous tissues, is a brain-specific metabolite (54,74). NAA metabolism involves different brain compartments, with neuronal mitochondria taking care of its biosynthesis via the activity of aspartate-N-acetyltransferase and oligodendrocytes contributing to its degradation via the activity of N-acetylaspartate acylase.…”

Section: Significance Of Posttraumatic Naa Reduction and Recoverymentioning

confidence: 99%

Temporal Window of Metabolic Brain Vulnerability to Concussion

et al. 2008

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OBJECTIVE:In the present study, the occurrence of the temporal window of brain vulnerability was evaluated in concussed athletes by measuring N-acetylaspartate (NAA) using proton magnetic resonance ( 1 H-MR) spectroscopy. METHODS: Thirteen nonprofessional athletes who had a sport-related concussive head injury were examined for NAA determination by means of 1 H-MR spectroscopy at 3, 15, and 30 days postinjury. All athletes but three suspended their physical activity. Those who continued their training had a second concussive event and underwent further examination at 45 days from the initial injury. The single case of one professional boxer, who was studied before the match and 4, 7, 15, and 30 days after a knockout, is also presented. Before each magnetic resonance examination, patients were asked for symptoms of mild traumatic brain injury, including physical, cognitive, emotional, and sleep disturbances. Data for 1 H-MR spectroscopy recorded in five normal, age-matched, control volunteers, who were previously screened to exclude previous head injuries, were used for comparison. Semiquantitative analysis of NAA relative to creatine (Cr)-and choline (Cho)-containing compounds was performed from proton spectra obtained with a 3-T magnetic resonance system. RESULTS: Regarding the values of the NAA-to-Cr ratio (2.21 Ϯ 0.11) recorded in control patients, singly concussed athletes, at 3 days after the concussion, showed a decrease of 18.5% (1.80 Ϯ 0.04; P Ͻ 0.001). Only a modest 3% recovery was observed at 15 days (1.88 Ϯ 0.1; P Ͻ 0.001); at 30 days postinjury, the NAA-to-Cr ratio was 2.15 Ϯ 0.1, revealing full metabolic recovery with values not significantly different from those of control patients. These patients declared complete resolution of symptoms at the time of the 3-day study. The three patients who had a second concussive injury before the 15-day study showed an identical decrease of the NAA-to-Cr ratio at 3 days (1.78 Ϯ 0.08); however, at 15 days after the second injury, a further diminution of the NAA-to-Cr ratio occurred (1.72 Ϯ 0.07; P Ͻ 0.05 with respect to singly concussed athletes). At 30 days, the NAAto-Cr ratio was 1.82 Ϯ 0.1, and at 45 days postinjury, the NAA-to-Cr ratio showed complete recovery (2.07 Ϯ 0.1; not significant with respect to control patients). This group of patients declared a complete resolution of symptoms at the time of the 30-day study. CONCLUSION: Results of this pilot study carried out in a cohort of singly and doubly concussed athletes, examined by 1 H-MR spectroscopy for their NAA cerebral content at different time points after concussive events, demonstrate that also in humans, concussion opens a temporal window of brain metabolic imbalance, the closure of which does not coincide with resolution of clinical symptoms. The recovery of brain metabolism is not linearly related to time. A second concussive event prolonged the time of NAA normalization by 15 days. Although needing confirmation in a larger group of patients, these results show that NAA measurement by 1 H-MR spe...

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Developmental Changes of N‐Acetyl‐L‐Aspartic Acid, N‐Acetyl‐α‐Aspartylglutamic Acid and β‐Citryl‐L‐Glutamic Acid in Different Brain Regions and Spinal Cords of Rat and Guinea Pig

Cited by 57 publications

References 14 publications

Metabolic studies of human primitive neuroectodermal tumour cells by proton nuclear magnetic resonance spectroscopy

Metabolic studies of human primitive neuroectodermal tumour cells by proton nuclear magnetic resonance spectroscopy

Molecular Identification of N-Acetylaspartylglutamate Synthase and β-Citrylglutamate Synthase

Temporal Window of Metabolic Brain Vulnerability to Concussion

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