glutaminase and Atrophy

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase (

Topics: Amino Acid Metabolism, Inborn Errors; Ataxia; Atrophy; Cerebellum; Child, Preschool; Developmental Disabilities; Female; Genotype; Glutaminase; Glutamine; Humans; Male; Microsatellite Repeats; Mutation; Phenotype; Polymerase Chain Reaction; Whole Genome Sequencing

Protein phosphatase 2ACα (PP2ACα), a vital member of the protein phosphatase family, has been studied primarily as a regulator for the development, growth and protein synthesis of a lot of cell types. Dysfunction of PP2ACα protein results in neurodegenerative disease; however, this finding has not been directly confirmed in the mouse model with PP2ACα gene knock-out. Therefore, in this study presented here, we generated the PP2ACα gene knock-out mouse model by the Cre-loxP targeting gene system, with the purpose to directly observe the regulatory role of PP2ACα gene in the development of mouse's cerebral cortex. We observe that knocking-out PP2ACα gene in the central nervous system (CNS) results in cortical neuronal shrinkage, synaptic plasticity impairments, and learning/memory deficits. Further study reveals that PP2ACα gene knock-out initiates Hippo cascade in cortical neuroprogenitor cells (NPCs), which blocks YAP translocation into the nuclei of NPCs. Notably, p73, directly targeted by Hippo cascade, can bind to the promoter of glutaminase2 (GLS2) that plays a dominant role in the enzymatic regulation of glutamate/glutamine cycle. Finally, we find that PP2ACα gene knock-out inhibits the glutamine synthesis through up-regulating the activity of phosphorylated-p73 in cortical NPCs. Taken together, it concludes that PP2ACα critically supports cortical neuronal growth and cognitive function via regulating the signaling transduction of Hippo-p73 cascade. And PP2ACα indirectly modulates the glutamine synthesis of cortical NPCs through targeting p73 that plays a direct transcriptional regulatory role in the gene expression of GLS2.

Topics: Animals; Atrophy; Cells, Cultured; Crosses, Genetic; Embryo, Mammalian; Genes, Reporter; Glutaminase; Hippocampus; Learning Disabilities; Malformations of Cortical Development; Memory Disorders; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins; Neural Stem Cells; Phosphorylation; Promoter Regions, Genetic; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; RNA Interference; Serine-Threonine Kinase 3; Signal Transduction; Tumor Protein p73

Branched-chain amino acid (BCAA)-enriched nutrient solutions reduce gut atrophy associated with parenteral nutrition. We hypothesized that this effect was mediated by phosphate-dependent glutaminase. Thirty male Wistar rats (300-350 g) underwent a standardized surgical procedure and were then randomized into three groups to receive 6 days of ad libitum enteral nutrition. The animals were fed a solution of conventional nutrients, a solution of conventional nutrients enriched with 2.0% BCAA or a solution of conventional parenteral nutrients enriched with 2.5% glutamine. When compared with rats fed conventional nutrients, rats fed BCAA and glutamine had less jejunal atrophy (P < 0.05) and a greater specific activity of phosphate-dependent glutaminase in the jejunum (131%; P < 0.05). It is concluded that enteral BCAA reduce atrophy of the jejunum via the generation of glutamine.

Topics: Amino Acids, Branched-Chain; Animals; Atrophy; Glutaminase; Glutamine; Jejunum; Male; Parenteral Nutrition; Rats; Rats, Wistar; Statistics, Nonparametric

Topics: Adult; Alanine; Amino Acid Metabolism, Inborn Errors; Amino Acids; Ammonia; Atrophy; Biological Transport; Blood Cell Count; Blood Glucose; Blood Urea Nitrogen; Bone Diseases; Brain Diseases; Dietary Proteins; Female; Glutaminase; Glutamine; Hemoglobins; Humans; Intellectual Disability; Kidney; Kidney Function Tests; Lysine; Metabolism, Inborn Errors; Nitrogen; Proteins; Specific Gravity; Urea; Urine