Persons with schizophrenia and other psychotic disorders have a high prevalence of obesity, impaired glucose tolerance, and lipid abnormalities, particularly hypertriglyceridemia and low high-density lipoprotein. More detailed molecular information on the metabolic abnormalities may reveal clues about the pathophysiology of these changes, as well as about disease specificity. We applied comprehensive metabolomics in serum samples from a general population-based study in Finland. The study included all persons with DSM-IV primary psychotic disorder (schizophrenia, n = 45; other non-affective psychosis (ONAP), n = 57; affective psychosis, n = 37) and controls matched by age, sex, and region of residence. Two analytical platforms for metabolomics were applied to all serum samples: a global lipidomics platform based on ultra-performance liquid chromatography coupled to mass spectrometry, which covers molecular lipids such as phospholipids and neutral lipids; and a platform for small polar metabolites based on two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC × GC-TOFMS). Compared with their matched controls, persons with schizophrenia had significantly higher metabolite levels in six lipid clusters containing mainly saturated triglycerides, and in two small-molecule clusters containing, among other metabolites, (1) branched chain amino acids, phenylalanine and tyrosine, and (2) proline, glutamic, lactic and pyruvic acids. Among these, serum glutamic acid was elevated in all psychoses (P = 0.0020) compared to controls, while proline upregulation (P = 0.000023) was specific to schizophrenia. After adjusting for medication and metabolic comorbidity in linear mixed models, schizophrenia remained independently associated with higher levels in seven of these eight clusters (P < 0.05 in each cluster). The metabolic abnormalities were less pronounced in persons with ONAP or affective psychosis. Our findings suggest that specific metabolic abnormalities related to glucoregulatory processes and proline metabolism are specifically associated with schizophrenia and reflect two different disease-related pathways. Metabolomics, which is sensitive to both genetic and environmental variation, may become a powerful tool in psychiatric research to investigate disease susceptibility, clinical course, and treatment response.

Metabolome in schizophrenia and other psychotic disorders: a general population-based study

The most common malignant brain tumors are those of astrocytic origin, gliomas, with the most aggressive glioblastoma (WHO grade IV) among them. Despite efforts, medicine has not made progress in terms of the prognosis and life expectancy of glioma patients. Behind the malignant phenotype of gliomas lies multiple genetic mutations leading to reprogramming of their metabolism, which gives those highly proliferating cells an advantage over healthy ones. The so-called glutamine addiction is a metabolic adaptation that supplements oxidative glycolysis in order to secure neoplastic cells with nutrients and energy in unfavorable conditions of hypoxia. The present review aims at presenting the research and clinical attempts targeting the different metabolic pathways involved in glutamine metabolism in gliomas. A brief description of the biochemistry of glutamine transport, synthesis, and glutaminolysis, etc. will forego a detailed comparison of the therapeutic strategies undertaken to inhibit glutamine utilization by gliomas.

Targeting Glutamine Addiction in Gliomas

In stress conditions, as neoplastic transformation, amino acids serve not only as nutrients to maintain the cell survival but also as mediators of several regulatory pathways which are involved in apoptosis and autophagy. Especially, under glucose deprivation, in order to maintain the cell survival, proline and glutamine together with other glutamine-derived products such as glutamate, alpha-ketoglutarate, and ornithine serve as alternative sources of energy. They are substrates for production of pyrroline-5-carboxylate which is the product of conversion of proline by proline dehydrogenase/ proline oxidase (PRODH/POX) to produce ATP for protective autophagy or reactive oxygen species for apoptosis. Interconversion of proline, ornithine, and glutamate may therefore regulate PRODH/POX-dependent apoptosis/autophagy. The key amino acid is proline, circulating between mitochondria and cytoplasm in the proline cycle. This shuttle is known as proline cycle. It is coupled to pentose phosphate pathway producing nucleotides for DNA biosynthesis. PRODH/POX is also linked to p53 and AMP-activated protein kinase (AMPK)-dependent pathways. Proline availability for PRODH/POX-dependent apoptosis/autophagy is regulated at the level of collagen biosynthesis (proline utilizing process) and prolidase activity (proline supporting process). In this review, we suggest that amino acid metabolism linking TCA and Urea cycles affect PRODH/POX-dependent apoptosis/autophagy and the knowledge might be useful to targeted cancer therapy.

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Understanding the role of key amino acids in regulation of proline dehydrogenase/proline oxidase (prodh/pox)-dependent apoptosis/autophagy as an approach to targeted cancer therapy.

Astrocyte energy and neurotransmitter metabolism in Alzheimer’s disease: Integration of the glutamate/GABA-glutamine cycle

Herein, we review the multifaceted roles of proline in cell biology. This peculiar cyclic imino acid is: (i) A main precursor of extracellular collagens (the most abundant human proteins), antimicrobial peptides (involved in innate immunity), salivary proteins (astringency, teeth health) and cornifins (skin permeability); (ii) an energy source for pathogenic bacteria, protozoan parasites, and metastatic cancer cells, which engage in extracellular-protein degradation to invade their host; (iii) an antistress molecule (an osmolyte and chemical chaperone) helpful against various potential harms (UV radiation, drought/salinity, heavy metals, reactive oxygen species); (iv) a neural metabotoxin associated with schizophrenia; (v) a modulator of cell signaling pathways such as the amino acid stress response and extracellular signal-related kinase pathway; (vi) an epigenetic modifier able to promote DNA and histone hypermethylation; (vii) an inducer of proliferation of stem and tumor cells; and (viii) a modulator of cell morphology and migration/invasiveness. We highlight how proline metabolism impacts beneficial tissue regeneration, but also contributes to the progression of devastating pathologies such as fibrosis and metastatic cancer.

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The Multifaceted Roles of Proline in Cell Behavior.

D-Serine acts as a co-agonist of N-methyl-D-aspartate receptors (NMDAR) which appear overactivated in AD, while D-aspartate is a modulatory molecule acting on NMDAR as a second agonist. The aim of this work is to clarify whether the levels of these D-amino acids in serum are deregulated in AD, with the final goal to identify novel and precocious biomarkers in AD. Serum levels of L- and D-enantiomers of serine and aspartate were determined by HPLC using a pre-column derivatization procedure and a selective enzymatic degradation. Experimental data obtained from age-matched healthy subjects (HS) and AD patients were statistically evaluated by considering age, gender, and disease progression, and compared. Minor changes were apparent in the serum L- and D-aspartate levels in AD patients compared to HS. A positive correlation for the D-serine level and age was apparent in the AD cohort. Notably, the serum D-serine level and the D-/total serine ratio significantly increased with the progression of the disease. Gender seems to have a minor effect on the levels of all analytes tested. This work proposes that the serum D-serine level and D-/total serine ratio values as novel and valuable biomarkers for the progression of AD: the latter parameter allows to discriminate CDR 2 and CDR 1 patients from healthy (CDR 0) individuals.

/pdf/serum-d-serine-levels-are-altered-in-early-phases-of-11w8aaqenn.pdf

Serum D-serine levels are altered in early phases of Alzheimer's disease: towards a precocious biomarker.

L-Proline is a multifunctional amino acid that plays an essential role in primary metabolism and physiological functions. Proline is oxidized to glutamate in the mitochondria and the FAD-containing enzyme proline oxidase (PO) catalyzes the first step in L-proline degradation pathway. Alterations in proline metabolism have been described in various human diseases, such as hyperprolinemia type I, velo-cardio-facial syndrome/Di George syndrome, schizophrenia and cancer. In particular, the mutation giving rise to the substitution Leu441Pro was identified in patients suffering of schizophrenia and hyperprolinemia type I. Here, we report on the expression of wild-type and L441P variants of human PO in a U87 glioblastoma human cell line in an attempt to assess their effect on glutamate metabolism. The subcellular localization of the flavoenzyme is not altered in the L441P variant, for which specific activity is halved compared to the wild-type PO. While this decrease in activity is significantly less than that previously proposed, an effect of the substitution on the enzyme stability is also apparent in our studies. At 24 hours of growth from transient transfection, the intracellular level of proline, glutamate, and glutamine is decreased in cells expressing the PO variants as compared to control U87 cells, reaching a similar figure at 72 h. On the other hand, the extracellular levels of the three selected amino acids show a similar time course for all clones. Furthermore, PO overexpression does not modify to a significant extent the expression of GLAST and GLT-1 glutamate transporters. Altogether, these results demonstrate that the proline pathway links cellular proline levels with those of glutamate and glutamine. On this side, PO might play a regulatory role in glutamatergic neurotransmission by affecting the cellular concentration of glutamate.

/pdf/proline-oxidase-controls-proline-glutamate-and-glutamine-4qixncl181.pdf

Proline oxidase controls proline, glutamate, and glutamine cellular concentrations in a U87 glioblastoma cell line.

Alzheimer's disease (AD), the main cause of dementia worldwide, is characterized by a complex and multifactorial etiology In large part, excitatory neurotransmission in the central nervous system is mediated by glutamate and its receptors are involved in synaptic plasticity The N-methyl-D-aspartate (NMDA) receptors, which require the agonist glutamate and a coagonist such as glycine or the D-enantiomer of serine for activation, play a main role here A second D-amino acid, D-aspartate, acts as agonist of NMDA receptors D-amino acids, present in low amounts in nature and long considered to be of bacterial origin, have distinctive functions in mammals In recent years, alterations in physiological levels of various D-amino acids have been linked to various pathological states, ranging from chronic kidney disease to neurological disorders Actually, the level of NMDA receptor signaling must be balanced to promote neuronal survival and prevent neurodegeneration: this signaling in AD is affected mainly by glutamate availability and modulation of the receptor's functions Here, we report the experimental findings linking D-serine and D-aspartate, through NMDA receptor modulation, to AD and cognitive functions Interestingly, AD progression has been also associated with the enzymes related to D-amino acid metabolism as well as with glucose and serine metabolism Furthermore, the D-serine and D-/total serine ratio in serum have been recently proposed as biomarkers of AD progression A greater understanding of the role of D-amino acids in excitotoxicity related to the pathogenesis of AD will facilitate novel therapeutic treatments to cure the disease and improve life expectancy

The Role of D-Amino Acids in Alzheimer's Disease.

http://www.cell.com/article/S2211124722010919/pdf

Insulin and serine metabolism as sex-specific hallmarks of Alzheimer's disease in the human hippocampus.

Human d-aspartate oxidase (hDASPO) is a FAD-dependent enzyme responsible for the degradation of d-aspartate (d-Asp). In the mammalian central nervous system, d-Asp behaves as a classical neurotransmitter, it is thought to be involved in neural development, brain morphology and behavior, and appears to be involved in several pathological states, such as schizophrenia and Alzheimer's disease. Apparently, the human DDO gene produces alternative transcripts encoding for three putative hDASPO isoforms, constituted by 341 (the 'canonical' form), 369, and 282 amino acids. Despite the increasing interest in hDASPO and its physiological role, little is known about these different isoforms. Here, the additional N-terminal peptide present in the hDASPO_369 isoform only has been identified in hippocampus of Alzheimer's disease female patients, while peptides corresponding to the remaining part of the protein were present in samples from male and female healthy controls and Alzheimer's disease patients. The hDASPO_369 isoform was largely expressed in E. coli as insoluble protein, hampering with its biochemical characterization. Furthermore, we generated U87 human glioblastoma cell clones stably expressing hDASPO_341 and, for the first time, hDASPO_369 isoforms; the latter protein showed a lower expression compared with the canonical isoform. Both protein isoforms are active (showing similar kinetic properties), localize to the peroxisomes, are very stable (a half-life of approximately 100 h has been estimated), and are primarily degraded through the ubiquitin-proteasome system. These studies shed light on the properties of hDASPO isoforms with the final aim to clarify the mechanisms controlling brain levels of the neuromodulator d-Asp.

Valentina Rabattoni

Papers

Serum D-serine levels are altered in early phases of Alzheimer's disease: towards a precocious biomarker.

Proline oxidase controls proline, glutamate, and glutamine cellular concentrations in a U87 glioblastoma cell line.

The Role of D-Amino Acids in Alzheimer's Disease.

Insulin and serine metabolism as sex-specific hallmarks of Alzheimer's disease in the human hippocampus.

Cellular studies of the two main isoforms of human d-aspartate oxidase.