Biosynthesis of N-acetylaspartate

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DESCRIPTION (provided by applicant): N-Acetylaspartate (NAA) is an abundant (5-10 mM) amino acid derivative of the nervous system, which is used clinically as a noninvasive marker for the functional integrity of neurons using magnetic resonance spectroscopy. Decreased degradation of NAA resulting from a congenital defect in the degradative enzyme aspartoacylase causes Canavan disease, an autosomal-recessive neurodegenerative disorder that develops after birth and results in death before 10 years of age. Other studies have shown decreases in NAA in specific neuronal systems in a number of neurological disorders, including schizophrenia. Importance of NAA in neuronal functions has been further emphasized by recent reports that show a strong association between NAA and cognitive ability and intelligence in humans. The long-term goal of this proposal is to determine the specific roles of NAA in neuronal functions. The central hypothesis is that NAA is an integral component of the glutamate oxidation system in neuronal mitochondria. The immediate objectives are to 1) purify the biosynthetic enzyme aspartate N-acetyltransferase from rat brain mitochondria and 2) generate antibodies against the enzyme and determine its cellular localization by immunohistochemistry. Toward these objectives, we have partially purified the enzyme from rat brain mitochondria and characterized it as a high molecular weight enzyme complex. The proposed studies would set the foundation for subsequent studies to test whether or not NAA mediates one or more neuronal functions, instead of serving merely as a marker for the functional integrity of neurons. Such studies should help to determine whether or not the decreases in NAA observed in neurological diseases, such as schizophrenia, play a role in their pathogenesis. Based on the above information, biochemical approaches aimed at replenishing the NAA could be developed as a novel therapeutic strategy.