{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNAT8L (also known as Shati/Nat8l) is a neuron‐specific N‐acetyltransferase that catalyzes the synthesis of N‐acetylaspartate (NAA) from L‐aspartate and acetyl‐coenzyme A. In neurons, the high concentration of NAA serves not only as a biomarker of neuronal health but also provides the acetyl group needed for lipid synthesis and energy metabolism. Mutations in NAT8L lead to a complete loss of functional NAA production and are linked to primary NAA deficiency, highlighting its critical role in maintaining neuronal integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its metabolic function, Shati/Nat8l plays a significant neuromodulatory role in the regulation of dopaminergic signaling and drug‐induced behavioral responses. Its expression in key brain regions—such as the nucleus accumbens and medial prefrontal cortex—is upregulated by methamphetamine exposure. Overexpression of Shati/Nat8l leads to increased production of NAA and its derivative, N-acetylaspartylglutamate (NAAG), which in turn activate group II metabotropic glutamate receptors to suppress excessive dopamine release. Complementary findings indicate that disruption of Shati/Nat8l not only enhances dopamine transmitter availability via altered receptor trafficking but also potentiates methamphetamine-induced hyperlocomotion and conditioned place preference."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond the central nervous system, NAT8L contributes to metabolic regulation in peripheral tissues. In adipose tissue, especially within brown adipocytes, NAT8L localizes to mitochondria and its overexpression promotes lipid turnover, enhances mitochondrial biogenesis, and upregulates thermogenic markers, thereby influencing energy homeostasis. Conversely, in hepatocellular carcinoma, reduced NAT8L expression rewires cellular metabolism by increasing cytosolic aspartate availability; this shift supports glucose flux into the pentose phosphate pathway and bolsters purine biosynthesis, ultimately facilitating cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nShati/Nat8l further impacts neuronal development, behavior, and cognitive function. Loss-of-function studies reveal that deficiency in Shati/Nat8l leads to altered neurogenesis, abnormal neuronal morphology in the hippocampus, and behavioral changes—including increased exploratory activity, reduced social interaction, and attentional deficits reminiscent of ADHD-like phenotypes. In aged mice, diminished Shati/Nat8l expression in the dorsal hippocampus correlates with cognitive decline, whereas its overexpression rescues these deficits, underscoring the enzyme’s potential as a therapeutic target in neurodevelopmental and age-associated cognitive disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "15"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in NAT8L expression are also implicated in neurodegenerative conditions. In Alzheimer’s disease models, dysregulation of NAT8L is associated with impaired mitochondrial oxidative phosphorylation and an altered balance in NAA metabolism, which may reflect a broader compensatory mechanism involving neuron-oligodendrocyte cross talk during cellular energetic crises."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elsa Wiame, Donatienne Tyteca, Nathalie Pierrot, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Deletion of SHATI/NAT8L decreases the N-acetylaspartate content in the brain and induces behavioral deficits, which can be ameliorated by administering N-acetylaspartate."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Neuropsychopharmacol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.euroneuro.2015.08.003"}], "href": "https://doi.org/10.1016/j.euroneuro.2015.08.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26361739"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26361739"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yoshiaki Miyamoto, Noriyuki Iegaki, Kequan Fu, et al. 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