The metabolic needs for postnatal growth of the human nervous system are vast. Recessive loss-of-function mutations in the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2) in humans cause postnatal undergrowth of brain, and cognitive and motor disability. We demonstrate that GPT2 governs critical metabolic mechanisms in neurons required for neuronal growth and survival. These metabolic processes include neuronal alanine synthesis and anaplerosis, the replenishment of tricarboxylic acid (TCA) cycle intermediates. We performed metabolomics across postnatal development in Gpt2-null mouse brain to identify the trajectory of dysregulated metabolic pathways: alterations in alanine occur earliest; followed by reduced TCA cycle intermediates and reduced pyruvate; followed by elevations in glycolytic intermediates and amino acids. Neuron-specific deletion of GPT2 in mice is sufficient to cause motor abnormalities and death pre-weaning, a phenotype identical to the germline Gpt2-null mouse. Alanine biosynthesis is profoundly impeded in Gpt2-null neurons. Exogenous alanine is necessary for Gpt2-null neuronal survival in vitro but is not needed for Gpt2-null astrocytes. Dietary alanine supplementation in Gpt2-null mice enhances animal survival and improves the metabolic profile of Gpt2-null brain but does not alone appear to correct motor function. In surviving Gpt2-null animals, we observe smaller upper and lower motor neurons in vivo. We also observe selective death of lower motor neurons in vivo with worsening motor behavior with age. In conclusion, these studies of the pathophysiology of GPT2 Deficiency have identified metabolic mechanisms that are required for neuronal growth and that potentially underlie selective neuronal vulnerabilities in motor neurons.

中文翻译：

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线粒体酶 GPT2 调节体内神经元生长和运动功能所需的代谢机制

人类神经系统出生后生长的代谢需求是巨大的。人类线粒体酶谷氨酸丙酮酸转氨酶 2 (GPT2) 的隐性功能丧失突变导致出生后大脑发育不全，以及认知和运动障碍。我们证明 GPT2 控制神经元生长和存活所需的神经元中的关键代谢机制。这些代谢过程包括神经元丙氨酸合成和回补，三羧酸 (TCA) 循环中间体的补充。我们在 Gpt2-null 小鼠大脑的出生后发育过程中进行了代谢组学，以确定代谢途径失调的轨迹：丙氨酸的改变最早发生；其次是减少的 TCA 循环中间体和减少的丙酮酸；其次是糖酵解中间体和氨基酸的升高。小鼠中 GPT2 的神经元特异性缺失足以导致运动异常和断奶前死亡，这是一种与生殖系 Gpt2 缺失小鼠相同的表型。Gpt2-null 神经元中丙氨酸的生物合成受到严重阻碍。外源性丙氨酸是 Gpt2-null 神经元体外存活所必需的，但 Gpt2-null 星形胶质细胞不需要。Gpt2-null 小鼠的膳食丙氨酸补充剂可提高动物存活率并改善 Gpt2-null 大脑的代谢特征，但似乎并不能单独纠正运动功能。在幸存的 Gpt2-null 动物中，我们在体内观察到较小的上下运动神经元。我们还观察到体内下运动神经元的选择性死亡，运动行为随着年龄的增长而恶化。综上所述，