Functions of N‐Acetyl‐l‐Aspartate and N‐Acetyl‐l‐Aspartylglutamate in the Vertebrate Brain

N‐Acetyl‐l‐aspartate (NAA) and its derivative N‐acetylaspartylglutamate (NAAG) are major osmolytes present in the vertebrate brain. Although they are synthesized primarily in neurons, their function in these cells is unclear. In the brain, these substances undergo intercompartmental cycles in which they are released by neurons in a regulated fashion and are then rapidly hydrolyzed by catabolic enzymes associated with glial cells. Recently, the catabolic enzyme for NAA hydrolysis has been found to be expressed only in oligodendrocytes, and the catabolic enzyme for NAAG expressed only in astrocytes. These results indicate an unusual tricellular metabolic sequence for the synthesis and hydrolysis of NAAG wherein it is synthesized in neurons from NAA and l‐glutamate, hydrolyzed to NAA and l‐glutamate by astrocytes, and further hydrolyzed to l‐aspartate and acetate by oligodendrocytes. Since the discovery that the NAA and NAAG anabolic products of neurons are specifically targeted to oligodendrocytes and astrocytes, respectively, this unique metabolic compartmentalization also suggests that these substances may play an important role in cell‐specific glial signaling. In this review, it is hypothesized that a key function of NAA and NAAG in the vertebrate brain is in cell signaling and that these substances are important in the regulation of interactions of brain cells and in the establishment and maintenance of the nervous system.

[1]  R. Kaul,et al.  Purification, Characterization, and Localization of Aspartoacylase from Bovine Brain , 1991, Journal of neurochemistry.

[2]  M. During,et al.  Global CNS gene transfer for a childhood neurogenetic enzyme deficiency: Canavan disease. , 1999, Current opinion in molecular therapeutics.

[3]  J. Coyle,et al.  Evidence for the presence of N-acetylaspartylglutamate in cultured oligodendrocytes and LPS activated microglia , 1998, Brain Research.

[4]  M. Baslow.  A Review of Phylogenetic and Metabolic Relationships Between the Acylamino Acids, N‐Acetyl‐l‐Aspartic Acid and N‐Acetyl‐l‐Histidine, in the Vertebrate Nervous System , 1997, Journal of neurochemistry.

[5]  N. Marks,et al.  Recent advances on neuronal caspases in development and neurodegeneration , 1999, Neurochemistry International.

[6]  J. Costerton,et al.  The involvement of cell-to-cell signals in the development of a bacterial biofilm. , 1998, Science.

[7]  W. Hess.  Localization of an open reading frame with homology to human aspartoacylase upstream from psbA in the prokaryote Prochlorococcus marinus CCMP 1375. , 1997, DNA sequence : the journal of DNA sequencing and mapping.

[8]  M. Baslow.  The existence of molecular water pumps in the nervous system: a review of the evidence , 1999, Neurochemistry International.

[9]  P. Divry,et al.  Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease. , 1989, American journal of medical genetics.

[10]  A. Ryo,et al.  Serial analysis of gene expression in a microglial cell line , 1999, Glia.

[11]  J. Coyle,et al.  Isolation and expression of a rat brain cDNA encoding glutamate carboxypeptidase II. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Matalon.  Canavan disease: diagnosis and molecular analysis. , 1997, Genetic testing.

[13]  M. Baslow.  Hypothesis: Molecular water pumps and the aetiology of Canavan disease: A case of the sorcerer's apprentice , 1999, Journal of Inherited Metabolic Disease.

[14]  J. Fawcett,et al.  N-Cadherin Inhibits Schwann Cell Migration on Astrocytes , 1999, Molecular and Cellular Neuroscience.

[15]  D. Jane,et al.  Pharmacological agents acting at subtypes of metabotropic glutamate receptors , 1999, Neuropharmacology.

[16]  A. Shaag,et al.  The spectrum of mutations of the aspartoacylase gene in Canavan disease in non-Jewish patients , 1999, Journal of Inherited Metabolic Disease.

[17]  I. Rapin,et al.  The clinical course of Canavan disease. , 1998, Pediatric neurology.

[18]  J. Coyle.  The Nagging Question of the Function ofN-Acetylaspartylglutamate , 1997, Neurobiology of Disease.

[19]  A. C. D. de Carvalho,et al.  Gap junction–mediated loops of neuronal‐glial interactions , 1998, Glia.

[20]  M. Santi,et al.  N‐acetylaspartylglutamate activates cyclic AMP‐coupled metabotropic glutamate receptors in cerebellar astrocytes , 1998, Glia.

[21]  H. Tallan.  Studies on the distribution of N-acetyl-L-aspartic acid in brain. , 1957, The Journal of biological chemistry.

[22]  井上 治久.  Serial analysis of gene expression in a microglial cell line , 2000 .

[23]  F. Tortella,et al.  Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury , 1999, Nature Medicine.

[24]  H. Tallan,et al.  N-Acetyl-L-aspartic acid in brain. , 1956, The Journal of biological chemistry.

[25]  William H. Oldendorf,et al.  N-Acetyl-L-Aspartic acid: A literature review of a compound prominent in 1H-NMR spectroscopic studies of brain , 1989, Neuroscience & Biobehavioral Reviews.

[26]  I. Black,et al.  Glutamate carboxypeptidase II is expressed by astrocytes in the adult rat nervous system , 1999, The Journal of comparative neurology.

[27]  E. Greenberg,et al.  Generation of cell-to-cell signals in quorum sensing: acyl homoserine lactone synthase activity of a purified Vibrio fischeri LuxI protein. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[28]  K. Bhakoo,et al.  In Vitro Expression of N‐Acetyl Aspartate by Oligodendrocytes , 2000, Journal of neurochemistry.

[29]  D. Allison,et al.  Extracellular products as mediators of the formation and detachment of Pseudomonas fluorescens biofilms. , 1998, FEMS microbiology letters.

[30]  J. Coyle,et al.  N-Acetylaspartate in neuropsychiatric disorders , 1995, Progress in Neurobiology.

[31]  R G Shulman,et al.  In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[32]  G. Fischbach,et al.  Axonal Neuregulin Signals Cells of the Oligodendrocyte Lineage through Activation of HER4 and Schwann Cells through HER2 and HER3 , 1997, The Journal of cell biology.

[33]  H. Tatsumi,et al.  Growth cones exhibit enhanced cell–cell adhesion after neurotransmitter release , 1999, Neuroscience.

[34]  B. Pettmann,et al.  Neuronal Cell Death , 1998, Neuron.

[35]  N-acetyl-aspartate: In-vitro expression in oligodendrocytes; implications for proton-MRS signal in vivo. , 2000 .

[36]  G. Sutherland,et al.  Labeling of N-acetylaspartate and N-acetylaspartylglutamate in rat neocortex, hippocampus and cerebellum from [1-13C]glucose , 1998, Neuroscience Letters.

[37]  M. Schwab,et al.  N-Acetylated alpha-linked acidic dipeptidase may be involved in axon-Schwann cell signalling , 1996, Journal of neurocytology.

[38]  J. Berger-Sweeney,et al.  Cholinergic regulation of cortical development and plasticity. New twists to an old story. , 1998, Perspectives on developmental neurobiology.

[39]  B. Popko.  Myelin galactolipids: Mediators of axon‐glial interactions? , 2000, Glia.

[40]  B. Iglewski,et al.  Active Efflux and Diffusion Are Involved in Transport of Pseudomonas aeruginosa Cell-to-Cell Signals , 1999, Journal of bacteriology.

[41]  J. Neale,et al.  Localization and Transport of N‐Acetylaspartylglutamate in Cells of Whole Murine Brain in Primary Culture , 1993, Journal of neurochemistry.

[42]  R. Matalon,et al.  Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease. , 1988, American journal of medical genetics.

[43]  T. Resnik,et al.  Canavan disease. Analysis of the nature of the metabolic lesions responsible for development of the observed clinical symptoms. , 1997, Journal of molecular neuroscience : MN.