N-acetylaspartate, or NAA, is the second most abundant metabolite in the human central nervous system (CNS). NAA is the acetylated form of the amino acid aspartate. The functional significance of the high NAA concentration in the brain remains uncertain, but it confers on NAA a unique clinical significance due to the fact that NAA emits the strongest signal in magnetic resonance spectrograms of the human brain. NAA levels measured by magnetic resonance spectroscopy are changed in a wide array of CNS disorders, but it is unknown if the changes are etiological, or merely secondary. Magnetic resonance spectroscopy (MRS) studies of human brain disorders have invariably detected decreases in brain NAA concentrations when neuronal loss or dysfunction are involved, with one major exception. The autosomal genetic disease, Canavan disease, involves the accumulation of NAA in the brain due to the lack of degradative enzyme activity. Virtually all other neurological disorders involving neuronal loss or dysfunction result in reductions in brain NAA levels including Alzheimer disease, epilepsy, amyotrophic lateral sclerosis, schizophrenia, multiple sclerosis, AIDS, traumatic brain injury, stroke and non-neuronal brain tumors such as glioma.
NAA is synthesized by an N-acetyltransferase enzyme (aspartate N-acetyltransferase) that is encoded by the gene NAT8L. NAA is metabolized to acetate and aspartate by the enzyme aspartoacylase (gene: ASPA). The functional significance of NAA synthesis and breakdown in the CNS are still not well understood, but it is known that NAA is required for the enzymatic synthesis of the neuropeptide N-acetylaspartylglutamate (NAAG). NAAG is involved in neuronal communcative functions such as neurotransmitter release modulation.
NAA has also been associated with lipid synthesis and myelination in the CNS, indicating that some of the acetate from NAA breakdown gets converted to acetyl CoA and is then incorporated into brain lipids. This process is most critical during postnatal brain development when myelination is taking place and myelin synthesis is maximal.
Recently, we have hypothesized that NAA is involved in gene transcriptional regulation through the concerted actions of three enzymes NAT8L (aspartate N-acetyltransferase), ASPA (aspartoacylase) and ACSS2 (acyl-CoA short chain synthetase-2), which we have termed the NAA-signaling pathway.
