NAA Synthesis
content is still dramatically lower than in control cells. Therefore, the likely aspartate synthesis stimulated by the increased glutamine consumption in Neuro2A cells with down-regulated AGC1 should not be sufficient to restore the NAA synthesis. This could be explained on one side by the preferable use of aspartate for proliferation processes, or on the other side by the lack of sufficient levels of acetylCoA, the second reagent, along with aspartate, of ANAT reaction. ANAT synthesizes NAA in neurons and its subcellular localization is still under debate; however, if NAA synthesis occurs in either mitochondria (Madhavarao et al., 2003) or microsomes (Lu et al., 2004), the main cell pathway that supplies acetyl groups is represented by the mitochondrial pyruvate
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As demonstrated in this thesis, pyruvate is preferentially consumed in the cytosol of the cells when AGC1 is down-regulated or impaired, thus limiting the mitochondrial production of acetylCoA and therefore the NAA synthesis by ANAT. Interestingly, in accordance with our hypothesis, it has been recently published that the first identified patient with AGC1 deficiency benefits from the administration of a ketogenic diet (Dahlin et al., 2015), usually used in therapies for intractable epilepsy, with resumed myelination and improved psychomotor activities. Whether the amelioration of the clinical picture of the patient is the secondary effect of this nutritional approach or the result of a specific and better provision of acetyl groups to neurons for the NAA synthesis, as in this thesis hypothesized, will deserve further
As demonstrated in this thesis, pyruvate is preferentially consumed in the cytosol of the cells when AGC1 is down-regulated or impaired, thus limiting the mitochondrial production of acetylCoA and therefore the NAA synthesis by ANAT. Interestingly, in accordance with our hypothesis, it has been recently published that the first identified patient with AGC1 deficiency benefits from the administration of a ketogenic diet (Dahlin et al., 2015), usually used in therapies for intractable epilepsy, with resumed myelination and improved psychomotor activities. Whether the amelioration of the clinical picture of the patient is the secondary effect of this nutritional approach or the result of a specific and better provision of acetyl groups to neurons for the NAA synthesis, as in this thesis hypothesized, will deserve further