Mitochondrial enzyme GPT2 regulates metabolic mechanisms required for neuron growth and motor function in vivo. Issue 4 (14th September 2021)

• Record Type: Journal Article
• Authors: Baytas, Ozan; Davidson, Shawn M; DeBerardinis, Ralph J; Morrow, Eric M
• Is Part Of: Human molecular genetics. Volume 31:Issue 4(2022)
• Page Start: 587
• Page End: 603
• Publication Date: 2021-09-14
• Subjects: Human molecular genetics -- Periodicals; Human chromosome abnormalities -- Periodicals; 572.8
• DOI: 10.1093/hmg/ddab269
• Languages: English
• ISSNs: 0964-6906

Abstract

Abstract: 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.