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Neurosci."],"published-print":{"date-parts":[[2020,11,25]]},"abstract":"<jats:p>Aralar\/AGC1\/Slc25a12, the mitochondrial aspartate-glutamate carrier expressed in neurons, is the regulatory component of the NADH malate-aspartate shuttle. AGC1 deficiency is a neuropediatric rare disease characterized by hypomyelination, hypotonia, developmental arrest, and epilepsy. We have investigated whether \u03b2-hydroxybutyrate (\u03b2OHB), the main ketone body (KB) produced in ketogenic diet (KD), is neuroprotective in<jats:italic>aralar<\/jats:italic>-knock-out (KO) neurons and mice. We report that \u03b2OHB efficiently recovers<jats:italic>aralar<\/jats:italic>-KO neurons from deficits in basal-stimulated and glutamate-stimulated respiration, effects requiring \u03b2OHB entry into the neuron, and protects from glutamate excitotoxicity.<jats:italic>Aralar<\/jats:italic>-deficient mice were fed a KD to investigate its therapeutic potential early in development, but this approach was unfeasible. Therefore,<jats:italic>aralar<\/jats:italic>-KO pups were treated without distinction of gender with daily intraperitoneal injections of \u03b2OHB during 5 d. This treatment resulted in a recovery of striatal markers of the dopaminergic system including dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC)\/DA ratio, and vesicular monoamine transporter 2 (VMAT2) protein. Regarding postnatal myelination, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) myelin proteins were markedly increased in the cortices of \u03b2OHB-treated<jats:italic>aralar<\/jats:italic>-KO mice. Although brain Asp and NAA levels did not change by \u03b2OHB administration, a 4-d \u03b2OHB treatment to<jats:italic>aralar<\/jats:italic>-KO, but not to control, neurons led to a substantial increase in Asp (3-fold) and NAA (4-fold) levels. These results suggest that the lack of increase in brain Asp and NAA is possibly because of its active utilization by the<jats:italic>aralar<\/jats:italic>-KO brain and the likely involvement of neuronal NAA in postnatal myelination in these mice. The effectiveness of \u03b2OHB as a therapeutic treatment in AGC1 deficiency deserves further investigation.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold><jats:italic>Aralar<\/jats:italic>deficiency induces a fatal phenotype in humans and mice and is associated with impaired neurodevelopment, epilepsy, and hypomyelination. In neurons, highly expressing<jats:italic>aralar<\/jats:italic>, its deficiency causes a metabolic blockade hampering mitochondrial energetics and respiration. Here, we find that \u03b2OHB, the main metabolic product in KD, recovers defective mitochondrial respiration bypassing the metabolic failure in<jats:italic>aralar<\/jats:italic>-deficient neurons. \u03b2OHB oxidation in mitochondria boosts the synthesis of cytosolic aspartate (Asp) and NAA, which is impeded by<jats:italic>aralar<\/jats:italic>deficiency, presumably through citrate-malate shuttle. In<jats:italic>aralar<\/jats:italic>-knock-out (KO) mice, \u03b2OHB recovers from the drastic drop in specific dopaminergic and myelin markers. The \u03b2OHB-induced myelin synthesis occurring together with the marked increment in neuronal NAA synthesis supports the role of NAA as a lipid precursor during postnatal myelination.<\/jats:p>","DOI":"10.1523\/jneurosci.0711-20.2020","type":"journal-article","created":{"date-parts":[[2020,10,21]],"date-time":"2020-10-21T21:50:18Z","timestamp":1603317018000},"page":"9293-9305","source":"Crossref","is-referenced-by-count":26,"title":["\u03b2OHB Protective Pathways in Aralar-KO Neurons and Brain: An Alternative to Ketogenic Diet"],"prefix":"10.1523","volume":"40","author":[{"given":"Irene","family":"P\u00e9rez-Li\u00e9bana","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda 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