Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases

Abstract

Amino acids are involved in various metabolic pathways and some of them also act as neurotransmitters. Since biosynthesis of L-glutamate and γ-aminobutyric acid (GABA) requires 2-oxoglutarate while 3-phosphoglycerate is the precursor of L-glycine and D-serine, evolutionary selection of these amino acid neurotransmitters might have been driven by their capacity to provide important information about the glycolytic pathway and Krebs cycle. Synthesis and recycling of amino acid neurotransmitters as well as composition and function of their receptors are often compromised in inherited metabolic diseases. For instance, increased plasma L-phenylalanine concentrations impair cerebral biosynthesis of protein and bioamines in phenylketonuria, while elevated cerebral L-phenylalanine directly acts via ionotropic glutamate receptors. In succinic semialdehyde dehydrogenase deficiency, the neurotransmitter GABA and neuromodulatory γ-hydroxybutyric acid are elevated. Chronic hyperGABAergic state results in progressive downregulation of GABA and GABA receptors and impaired mitophagy. In glycine encephalopathy, the neurological phenotype is precipitated by L-glycine acting both via cortical NMDA receptors and glycine receptors in spinal cord and brain stem neurons. Serine deficiency syndromes are biochemically characterized by decreased biosynthesis of L-serine, an important neurotrophic factor, and the neurotransmitters D-serine and L-glycine. Supplementation with L-serine and L-glycine has a positive effect on seizure frequency and spasticity, while neurocognitive development can only be improved if treatment starts in utero or immediately postnatally. With novel techniques, the study of synaptic dysfunction in inherited metabolic diseases has become an emerging research field. More and better therapies are needed for these difficult-to-treat diseases.

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

“…Gln is then shuttled back to presynaptic GABAergic neurons via glutamine transporter SLC38A3 (SN1) and glutamine transporter SLC38A2 (GLNT). In SSADH-D, SSA cannot be converted to succinate but is reduced to GHB by SSA reductase (SSAR) (adapted from [15,16]).…”

Sex-specific metabolic alterations in the type 1 diabetic brain of mice revealed by an integrated method of metabolomics and mixed-model

“…In addition, using multi-tissue metabolomics analysis, we previously revealed that the levels of glutamate and glutamine were significantly reduced in the kidney of male mice during T1D development, but not in female mice [34] . Aspartate and glycine are two major amino acid neurotransmitters in multiple brain regions [56] and serve as a selective agonist for N-methyl- d -aspartate (NMDA) receptors, which has also been associated with cognitive functions [57] . Relative to female mice, we detected a higher level of aspartate in the midbrain and higher glycine in the cortex, striatum and cerebellum in male mice.…”

Examining the blood amino acid status in pretherapeutic patients with hyperphenylalaninemia

“…8,15 Increased cerebral Phe competes with Gly and Glu for their receptors, changing the levels of receptor expression and thus influencing the synaptic function. 16 A previous study reported that the glutamatergic synaptic transmission in the brain is impaired in patients with PKU. 17 PKU patients have reduced myelin formation and dopamine levels.…”

“…In PKU, elevated plasma Phe levels impair the transport of other LNAAs, resulting in cerebral depletion of LNAA and hence decreased biosynthesis of protein and impaired brain function . Increased cerebral Phe competes with Gly and Glu for their receptors, changing the levels of receptor expression and thus influencing the synaptic function . A previous study reported that the glutamatergic synaptic transmission in the brain is impaired in patients with PKU .…”