Evidence that the tri-cellular metabolism of N-acetylaspartate functions as the brain’s “operating system”: how NAA metabolism supports meaningful intercellular frequency-encoded communications

Baslow, Morris H.

doi:10.1007/s00726-010-0656-6

Cited by 56 publications

(53 citation statements)

References 24 publications

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“…Both metabolites take part in a brain metabolic cycle that includes synthesis of NAAG in neurons, breakdown of NAAG to NAA and glutamate in association with astrocytes, and breakdown of NAA into aspartate and acetate in oligodendrocytes (24,26). The finding that NAA and NAAG are lowered in cell lines homologously expressing IDH mutants and also in human glioma tissues with IDH1 mutations suggests that glioma cell lines homologously expressing IDH mutants recapitulate features of human gliomas with somatic IDH mutations in situ.…”

Section: Glioma Cells Expressing Idh1-r132h Share Metabolomic Featurementioning

confidence: 74%

Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome

Reitman

Jin

Karoly

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

404

407

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Point mutations of the NADP + -dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1-and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations.ifferences in cellular metabolism between cancer and normal cells have long been noted by cancer researchers (1). Genetic alterations that occur in cancer, such as mutations and copy number changes that alter K-Ras and c-Myc, are thought to be responsible for at least some of these metabolic differences (2, 3). The genetic alterations that drive cancer pathogenesis may do so in part by deregulating cellular metabolism. Such deregulation could aberrantly signal cells to proliferate and provide molecular building blocks for cellular replication (4). This possibility has generated enthusiasm for the idea that that drug targets for the specific killing of cancer cells can be identified by studying the metabolic differences between normal and cancer cells.Gliomas are tumors of the central nervous system that respond poorly to therapy and are associated with a heterogeneous collection of genetic alterations (5, 6), including mutations in IDH1 and IDH2 (7,8). IDH1 and IDH2 are the cytoplasmic and mitochondrial NADP + -dependent isocitrate dehydrogenases, respectively, and are homologs. Isocitrate dehydrogenase 3 (IDH3), which is unrelated to IDH1 and IDH2, is a NAD + -dependent isocitrate dehydrogenase and has not been found to be mutated in cancer (Fig. S1A). These enzymes convert isocitrate to α-ketoglutarate (Fig. S1B). IDH1 catalyzes this reaction in the cytosol and peroxisome to mediate a variety of cellular housekeeping functions, whereas IDH2 and IDH3 catalyze a step in the tricarboxylic acid (TCA) cycle (reviewed in ref. 9). IDH1-R132 mutations occur frequently (50-93%) in astrocytomas and oligodendrogliomas, as well as in secondary glioblastomas, and may be the initiating lesion in these glioma subtypes (7,8). Mutations in the analogous IDH2-R172 codon also occur at a lower rate (3-5%) in these cancers (8). Interestingly, mutations in IDH1 and IDH2 were observed subsequently in 22% of ac...

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Section: Glioma Cells Expressing Idh1-r132h Share Metabolomic Featurementioning

confidence: 74%

Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome

Reitman

Jin

Karoly

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

404

407

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“…2). 18 Both NAA and NAAG are synthesized in the neuron, but neither are catabolized in the neuron itself. NAA is either released from neurons or is transported to oligodendrocytes, where it is metabolized into acetate and aspartate by aspartoacylase (ASPA).…”

Section: Tricellular Compartment Metabolism Of Naamentioning

confidence: 99%

N-acetylaspartate Decrease in Acute Stage of Ischemic Stroke:A Perspective from Experimental and Clinical Studies

et al. 2015

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N-acetylaspartate (NAA) appears in a prominent peak in proton magnetic resonance spectroscopy ( 1 H-MRS) of the brain. Exhibition by NAA of time-dependent attenuation that reflects energy metabolism during the acute stage of cerebral ischemia makes this metabolite a unique biomarker for assessing ischemic stroke. Although magnetic resonance (MR) imaging is a powerful technique for inspecting the pathological changes that occur during ischemic stroke, biomarkers that directly reflect the drastic metabolic changes associated with acute-stage ischemia are strongly warranted for appropriate therapeutic decision-making in daily clinical settings. In this review, we provide a brief overview of NAA metabolism and focus on the use of attenuation in NAA as a means for assessing the pathophysiological changes that occur during the acute stage of ischemic stroke.

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“…Toxicological assessment of changed levels in natural constituents 21 The applicant provided published information on NAA, NAG, N-acetylserine (NAS), Nacetylthreonine (NAT) and N-acetylglycine (NAGly) and the full reports of the available toxicological studies. A summary of these studies has been published by Delaney et al (2008), Harper et al (2009 and2010), Karaman et al (2009) and van de Mortel et al (2010aand 2010b.…”

Section: (D) Repeated-dose Toxicity Testingmentioning

confidence: 99%

“…NAA is synthesised in brain neurons and has important roles in the function of the central nervous system. However, NAA must be released by neurons into the extracellular fluid from where it is taken up by glial cells to be hydrolysed to aspartic and acetic acid (Baslow, 2003(Baslow, , 2010. NAA of a different origin occurs also in other organs.…”

Section: Information On Naa and Nagmentioning

confidence: 99%

Scientific Opinion on application (EFSA‐GMO‐UK‐2008‐53) for the placing on the market of herbicide tolerant genetically modified maize 98140 for food and feed uses, import and processing under Regulation (EC) No 1829/2003 from Pioneer Overseas Corporation

2013

EFS2

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Maize 98140 contains a single insert consisting of the gat4621 and the Zm-hra expression cassettes, providing herbicide tolerance. Bioinformatic analyses and genetic stability studies did not raise safety issues. The levels of the GAT and Zm-HRA protein in maize 98140 have been sufficiently analysed. The minimum standards for the design of field trials, set out in the EFSA GMO Panel guidance document, were not met. Therefore the EFSA GMO Panel was not in a position to conclude on the comparative assessment of the compositional, agronomic and phenotypic characteristics, on the basis of the data provided. In the absence of conclusions on the comparative assessment of composition, the risk assessment was restricted to the newly expressed proteins and to specific metabolites resulting from the acetylase activity of the GAT4621 protein. The EFSA GMO Panel has identified a gap in the data on the agronomic and phenotypic characterisation of GM maize 98140 and considers that uncertainty over these characteristics remains. However, considering the scope of this application, the available data and the poor survival capacity of maize outside cultivated land, the EFSA GMO Panel concluded that there is very little likelihood of environmental effects due to the accidental release into the environment of viable grains from maize 98140. Considering its intended use as food and feed, interactions with the biotic and abiotic environment were not considered to be an issue. Risks associated with an unlikely but theoretically possible horizontal gene transfer from maize 98140 to bacteria have not been identified. The monitoring plan and reporting intervals were in line with the intended uses of maize 98140. ABSTRACTMaize 98140 contains a single insert consisting of the gat4621 and the Zm-hra expression cassettes, providing herbicide tolerance. Bioinformatic analyses and genetic stability studies did not raise safety issues. The levels of the GAT and Zm-HRA protein in maize 98140 have been sufficiently analysed. The minimum standards for the design of field trials, set out in the EFSA GMO Panel guidance document, were not met. Therefore the EFSA GMO Panel was not in a position to conclude on the comparative assessment of the compositional, agronomic and phenotypic characteristics, on the basis of the data provided. In the absence of conclusions on the comparative assessment of composition, the risk assessment was restricted to the newly expressed proteins and to specific metabolites resulting from the acetylase activity of the GAT4621 protein. The EFSA GMO Panel has identified a gap in the data on the agronomic and phenotypic characterisation of GM maize 98140 and considers that uncertainty over these characteristics remains. However, considering the scope of this application, the available data and the poor survival capacity of maize outside cultivated land, the EFSA GMO Panel concluded that there is very little likelihood of environmental effects due to the accidental release into the environment of viable grains from ma...

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Evidence that the tri-cellular metabolism of N-acetylaspartate functions as the brain’s “operating system”: how NAA metabolism supports meaningful intercellular frequency-encoded communications

Cited by 56 publications

References 24 publications

Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome

Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome

N-acetylaspartate Decrease in Acute Stage of Ischemic Stroke:A Perspective from Experimental and Clinical Studies

Scientific Opinion on application (EFSA‐GMO‐UK‐2008‐53) for the placing on the market of herbicide tolerant genetically modified maize 98140 for food and feed uses, import and processing under Regulation (EC) No 1829/2003 from Pioneer Overseas Corporation

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