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The discrepant expression of NAA and ASPA in neurons and oligodendrocytes respectively, has been proposed as a mechanism for channeling NAA-associated acetate from neurons to oligodendrocytes.34 Based on this, and many findings from laboratories around the world, as well as the results of ongoing studies in our laboratory, we propose an expanded model of NAA metabolism wherein NAA has multiple roles in the nervous system (Figure 4).42,51 In neurons, the NAA biosynthetic enzyme Asp-NAT acts to remove excess aspartate from mitochondria via acetylation, which would favor a-ketoglutarate formation from glutamate, and energy production via the citric acid cycle. By this mechanism, the extra demand for ATP in neurons is met in part by oxidation of glutamate via the aspartate aminotransferase pathway.52 The high concentrations of NAA

Figure 4. Diagrammatic representation of NAA synthesis in neurons and degradation in oligodendrocytes. See text for details. OAA = oxaloacetic acid, AAT = aspartate aminotransferase, Asp-NAT = aspartate N-acetyltransferase, PDH = pyruvate dehydrogenase, a-KG = alphaketoglutarate, GDH = glutamate dehydrogenase, F.A. = fatty acids.

Figure 4. Diagrammatic representation of NAA synthesis in neurons and degradation in oligodendrocytes. See text for details. OAA = oxaloacetic acid, AAT = aspartate aminotransferase, Asp-NAT = aspartate N-acetyltransferase, PDH = pyruvate dehydrogenase, a-KG = alphaketoglutarate, GDH = glutamate dehydrogenase, F.A. = fatty acids.

in neurons, and the steady-state levels maintained there, would reflect the metabolic state of neuronal mitochondria because of the direct coupling of NAA production to a-ketoglutarate formation from glutamate. By preferentially using the aspartate aminotransferase reaction instead of the glutamate dehydrogenase reaction to generate a-ketoglutarate, neuronal mitochondria would prevent ammonia production associated with the glutamate dehydrogenase reaction, and this might avoid additional metabolic stress on neurons. In this model, NAA synthesis is intimately associated with the proper functioning of neuronal energy metabolism via the aspartate aminotransferase reaction in neuronal mitochondria. Further, NAA synthesized in neuronal mitochondria is transferred to oligodendrocytes by an as yet unknown mechanism, where ASPA liberates the acetate moiety to be used for myelin lipid synthesis. This hypothesis emphasizes the metabolic coupling of myelinated axons to oligodendrocytes, where axons provide major biochemical precursors for the demanding task of myelination during early postnatal CNS development. Whether the liberated aspartate is predominantly utilized in oligodendrocytes for metabolism and protein synthesis, or is instead recycled in great part back to neurons for a new cycle of NAA synthesis, is presently unknown.

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