Introduction

The First International Symposium on W-acetylaspartate (NAA) was held on September 13th and 14th, 2004 in the Natcher Conference Center at the NIH, in Bethesda Maryland. The event showed clearly that NAA was no longer an obscure object of study by a few scattered researchers, and that instead it had become a subject of great interest to hundreds of scientists and clinicians from around the world. This newfound attention for one of the brain's most concentrated amino acid derivatives was a long time in coming, since the first report of NAA in the brains of cats and rats by Tallan and coworkers in 1956.1 The Symposium also covered W-acetylaspartylglutamate (NAAG), a related dipeptide comprised of NAA and glutamate, which was first identified definitively as a brain-specific peptide by Miyamoto and colleagues in 1966.2 Despite decades of research on the roles both these molecules play in the nervous system, their functions remain enigmatic, and controversial.

NAA in particular is a study in controversy, with virtually no consensus on its principle metabolic or neurochemical functions after nearly five decades of research. There is relative unanimity on one point; NAA is not thought to be a neurotransmitter or neuromodulator that is released synaptically upon neuronal depolarization. Beyond that, there is little consensus. At least four basic hypotheses have been offered for the principle role of NAA in the nervous system: 1) an organic osmolyte that counters the "anion deficit" in neurons, or a co-transport substrate for a proposed "molecular water pump" that removes metabolic water from neurons, 2) a source of acetate for myelin lipid synthesis in oligodendrocytes, 3) an energy source in neurons, and 4) a precursor for the biosynthesis of NAAG. These functions are not mutually exclusive, and indeed, NAA certainly serves multiple functions in the nervous system.

The two findings that catapulted NAA into mainstream scientific consciousness were the connection to the fatal hereditary genetic disorder known as Canavan disease, and the

Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda MD, 20814 USA; email, [email protected].

prominence of the NAA-signal in magnetic resonance spectroscopy (MRS). In the case of Canavan disease, it was found that a mutation in the gene for the enzyme aspartoacylase (ASPA) resulted in the inability to remove acetate from NAA, leading to a failure of CNS myelination, and preventing CNS maturation. In the case of the prominent NAA signal in MRS, it has been found that the levels of NAA in various parts of the brain correlated with neuronal health or dysfunction. Low levels of NAA as detected by MRS have been interpreted to indicate neuronal/axonal loss, or compromised neuronal metabolism. High levels of brain NAA were found in many Canavan patients, suggesting that excess NAA may have toxic effects in the CNS. The First International Symposium on NAA covered these, and many other issues involving the roles played by NAA in normal and pathological brain function. The following sections briefly outline several of the various hypotheses proposed by different research groups on the possible functions of NAA in the nervous system.

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