Loss of mitochondrial enzyme GPT2 causes early neurodegeneration in locus coeruleus.

Locus coeruleus (LC) is among the first brain areas to degenerate in Alzheimer's disease and Parkinson's disease; however, the underlying causes for the vulnerability of LC neurons are not well defined. Here we report a novel mechanism of degeneration of LC neurons caused by loss of the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). GPT2 Deficiency is a newly-recognized childhood neurometabolic disorder. The GPT2 enzyme regulates cell growth through replenishment of tricarboxylic acid (TCA) cycle intermediates and modulation of amino acid metabolism. In Gpt2- null mice, we observe an early loss of tyrosine hydroxylase (TH)-positive neurons in LC and reduced soma size at postnatal day 18. Gpt2- null LC shows selective positive Fluoro-Jade C staining. Neuron loss is accompanied by selective, prominent microgliosis and astrogliosis in LC. We observe reduced noradrenergic projections to and norepinephrine levels in hippocampus and spinal cord. Whole cell recordings in Gpt2- null LC slices show reduced soma size and abnormal action potentials with altered firing kinetics. Strikingly, we observe early decreases in phosphorylated S6 in Gpt2- null LC, preceding prominent p62 aggregation, increased LC3B-II to LC3B-I ratio, and neuronal loss. These data are consistent with a possible mechanism involving deficiency in protein synthesis and cell growth, associated subsequently with abnormal autophagy and neurodegeneration. As compared to the few genetic animal models with LC degeneration, loss of LC neurons in Gpt2- null mice is developmentally the earliest. Early neuron loss in LC in a model of human neurometabolic disease provides important clues regarding the metabolic vulnerability of LC and may lead to new therapeutic targets. • GPT2 loss causes early neurodegeneration, gliosis and neuron loss in locus coeruleus. • Norepinephrine levels and innervation are reduced in Gpt2 -null central nervous system. • Electrophysiological properties of Gpt2 -null locus coeruleus neurons are altered. • Decreases in pS6 precede p62 aggregation and neuron loss in Gpt2 -null locus coeruleus. • Autophagy indicator, LC3B-II/LC3B-I ratio is increased in Gpt2 -null locus coeruleus. [ABSTRACT FROM AUTHOR]

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