The role of glutamate pyruvate transaminase 2 (GPT2) in neurometabolism and molecular mechanisms of GPT2 Deficiency

Baytas, Ozan

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Year:: 2021
Contributor:: Baytas, Ozan (creator); Berson, David (Reader); Liu, Judy (Reader); Morrow, Eric (Advisor); Abel, Ted (Reader); Brown University. Department of Neuroscience (sponsor)
Genre:: theses
Subject:: Glutamic acid; Locus coeruleus; Neurogenetics; Neurodegeneration; motor deficits; Spinal cord; GPT2; Alanine--Metabolism; TCA cycle; neurometabolism; postnatal microcephaly; spastic paraplegia; Intellectual disability
Extent:: 13, 497 p.

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Abstract:: Recessive loss-of-function mutations in the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2) in humans cause reduced postnatal brain growth, and cognitive and motor disability. GPT2 catalyzes the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and alpha-ketoglutarate. We demonstrate that GPT2 governs critical metabolic mechanisms in neurons required for neuronal growth and survival in a mouse model of GPT2 Deficiency. These metabolic processes include neuronal alanine synthesis and anaplerosis, the replenishment of tricarboxylic acid (TCA) cycle intermediates. By targeted metabolomics, we find alterations in alanine levels to occur earliest, followed by reduced TCA cycle intermediates and reduced pyruvate. Neuron-specific deletion of Gpt2 in mice is sufficient to cause motor abnormalities and death pre-weaning, a phenotype identical to the germ-line 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. In surviving Gpt2-null animals, we observe smaller upper and lower motor neurons in vivo. We observe selective death of lower motor neurons in vivo with worsening motor behavior with age. GPT2 Deficiency also involves a novel mechanism of degeneration, gliosis, and neuron loss in locus coeruleus with reduced noradrenergic projections to and norepinephrine levels in hippocampus and spinal cord in Gpt2-null mice. We report that GPT2 is enriched in isolated synaptic terminals and GPT2 loss leads to reprogramming of glutamate metabolism. Glutamatergic transmission in Gpt2-null CA1 hippocampal slices is impaired. Glutamate levels released from Gpt2-null isolated nerve terminals are reduced but restored to wild-type levels by alpha-ketoglutarate. These studies of the pathophysiology of GPT2 Deficiency have identified metabolic mechanisms that are required for neuronal growth and that may underlie selective vulnerabilities in specific neuronal circuits. Alanine or TCA cycle supplementation may also prove useful as therapeutic targets in patients with GPT2 Deficiency.
Notes:: Thesis (Ph. D.)--Brown University, 2021

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Citation

Baytas, Ozan, "The role of glutamate pyruvate transaminase 2 (GPT2) in neurometabolism and molecular mechanisms of GPT2 Deficiency" (2021). Neuroscience Theses and Dissertations. Brown Digital Repository. Brown University Library. https://repository.library.brown.edu/studio/item/bdr:maj44gye/

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Neuroscience Theses and Dissertations

Theses and Dissertations for the Neuroscience department.
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