Cholinergic neurons like the other ones may synthesize N-acetylL-aspartate (NAA), which serves as a source for acetyl units for lipid synthesis in oligodendroglial cells. Pyruvate-derived acetylCoA is a substrate for NAA synthesis in aspartoacylase reaction in the mitochondrial and cytoplasmic compartments of neuronal cells. Highly differentiated cholinergic neurons were found to be more susceptible to neurodegenerative signals due to relative shortage of acetyl-CoA in the former ones. It gives rise to hypothesis that in cholinergic neurons, NAA synthesizing pathway might compete for acetyl-CoA with acetylcholine synthesis and energy producing pathways in their cytoplasmic and mitochondrial compartments, respectively. Therefore, the aim of this work was to investigate whether neurotoxic conditions that inhibit acetyl-CoA synthesis alter interactions between acetylcholine and NAA metabolism in neurons of low and high expression of the cholinergic phenotype. The differentiation of SN56 cholinergic neuroblastoma cells with cAMP and retinoic acid caused 30% increase of NAA content and 100% elevation of intracellular acetylcholine content and its synthesis. Simultaneously, the decrease of mitochondrial and increase of cytoplasmic acetyl-CoA levels were observed, respectively. Inhibition of pyruvate dehydrogenase activity by amprolium-evoked thiamine pyrophosphate deficit, brought about concentration-dependent suppression of acetyl-CoA content both in mitochondrial and cytoplasmic compartments along with inhibition of acetylcholine synthesis/ release. However, NAA content was affected by these conditions neither in nondifferentiated nor in differentiated cells. On the other hand, acetylcholine synthesis was stronger inhibited in differentiated than in nondifferentiated cells. Zinc (0.15 mM) and L-aspartate (1.0 mM) increased NAA level but inhibited acetylcholine synthesis and decreased cell viability and their acetyl-CoA content. These alterations were more evident in differentiated than in nondifferentiated cells. These data indicate that NAA metabolism may compete with acetylcholine sythesis for common precursor - acetyl-CoA thereby negatively affecting their chance for survival in different neurodegenerative conditions. Work was supported by MNiSW projects NN401233333, NN401029937 and GUMed St57 fund.
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