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Biomolecules
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Alterations in D-amino Acid Metabolism in Psychiatric and Neurological Disorders
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Alterations in D-amino Acid Metabolism in Psychiatric and Neurological Disorders

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (10 March 2023) | Viewed by 9301

Special Issue Editors

Prof. Dr. Alessandro Usiello

E-Mail Website
Guest Editor
1. Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania, 81100 Caserta, Italy
2. Laboratory of Behavioral Neuroscience, Ceinge Biotecnologie Avanzate, 80145 Naples, Italy
Interests: D-amino acids metabolism; NMDA signaling; schizophrenia; cognition; synaptic plasticity
Dr. Francesco Errico

E-Mail Website
Guest Editor
Department of Agricultural Sciences, University of Naples “Federico II”, 80138 Naples, Italy
Interests: D-amino acids metabolism; nutrition; NMDA signaling; brain aging; schizophrenia

Special Issue Information

Dear Colleagues,

All amino acids, except glycine, have a chiral carbon center that allows for the formation of two stereoisomers that are mirror images of each other. However, despite the potential to exist as both left-handed (L) and right-handed (D) forms, animal organisms exclusively use L-amino acids as building blocks of proteins and intermediates of biochemical processes. In this context, the free D-amino acids identified for the first time between the 1980s and the 1990s in biological tissues of mammals, including humans, were initially considered a by-product derived from the diet and/or the intestinal bacterial flora. However, the recent discovery of enzymes involved in free D-amino acids biosynthesis, along with the long-established existence of enzymes responsible for selective D-amino acid degradation, have led to the hypothesis that these “unusual” molecules might have a role in the biology of mammals. To date, several D-amino acids have been identified in the mammalian brain and peripheral organs. Among them, D-serine and D-aspartate have been reported to occur in larger amounts and to emerge in a time- and tissue-dependent manner. In the central nervous system, D-serine and D-aspartate bind to the N-methyl D-aspartate (NMDA) subtype of glutamate receptors, the former as a co-agonist at the glycine binding site, the latter as a direct agonist at the glutamate binding site. In the light of their respective pharmacological abilities, different studies in animal models and humans have shown that these D-amino acids are able to modulate different NMDA receptor-dependent processes, including synaptic plasticity, brain development and cognition. It is well known that NMDA receptors are also implicated in brain aging, and their dysfunctional activity is relevant to the etiology and pathophysiology of a wide range of psychiatric and neurological disorders, including schizophrenia, autism, depression, addiction, amyotrophic lateral sclerosis, multiple sclerosis and neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. Given their neuromodulatory influence on NMDA receptors, different studies have recently evaluated the involvement of D-serine and D-aspartate in some of the abovementioned disorders, finding a dysregulated metabolism of these molecules and hypothesizing, in some instances, a potential role as biomarkers or therapeutic agents. These issues, however, are still matter of debate within the scientific community.

Based on this bulk of evidence and on the still unresolved questions, in this Special Issue, we invite scientists to submit original research articles and review articles exploring the role of D-serine, D-aspartate and possibly other D-amino acids in the neurobiology and in neuropathology of psychiatric and neurological disorders.

Prof. Dr. Alessandro Usiello
Dr. Francesco Errico
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurological disorders
  • psychiatric disorders
  • NMDA receptors
  • D-aspartate
  • D-serine

Published Papers (4 papers)

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Research

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16 pages, 2091 KiB  
Article
Phosphoserine Aminotransferase Pathogenetic Variants in Serine Deficiency Disorders: A Functional Characterization
by Francesco Marchesani, Annalisa Michielon, Elisabetta Viale, Annalisa Bianchera, Davide Cavazzini, Loredano Pollegioni, Giulia Murtas, Andrea Mozzarelli, Stefano Bettati, Alessio Peracchi, Barbara Campanini and Stefano Bruno
Biomolecules 2023, 13(8), 1219; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13081219 - 04 Aug 2023
Cited by 1 | Viewed by 918
Abstract
In humans, the phosphorylated pathway (PP) converts the glycolytic intermediate D-3-phosphoglycerate (3-PG) into L-serine through the enzymes 3-phosphoglycerate dehydrogenase, phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase. From the pathogenic point of view, the PP in the brain is particularly relevant, as genetic defects of [...] Read more.
In humans, the phosphorylated pathway (PP) converts the glycolytic intermediate D-3-phosphoglycerate (3-PG) into L-serine through the enzymes 3-phosphoglycerate dehydrogenase, phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase. From the pathogenic point of view, the PP in the brain is particularly relevant, as genetic defects of any of the three enzymes are associated with a group of neurometabolic disorders known as serine deficiency disorders (SDDs). We recombinantly expressed and characterized eight variants of PSAT associated with SDDs and two non-SDD associated variants. We show that the pathogenetic mechanisms in SDDs are extremely diverse, including low affinity of the cofactor pyridoxal 5′-phosphate and thermal instability for S179L and G79W PSAT, loss of activity of the holo form for R342W PSAT, aggregation for D100A PSAT, increased Km for one of the substrates with invariant kcats for S43R PSAT, and a combination of increased Km and decreased kcat for C245R PSAT. Finally, we show that the flux through the in vitro reconstructed PP at physiological concentrations of substrates and enzymes is extremely sensitive to alterations of the functional properties of PSAT variants, confirming PSAT dysfunctions as a cause of SSDs. Full article
(This article belongs to the Special Issue Alterations in D-amino Acid Metabolism in Psychiatric and Neurological Disorders)
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17 pages, 3500 KiB  
Article
ASC Transporters Mediate D-Serine Transport into Astrocytes Adjacent to Synapses in the Mouse Brain
by Karthik Subramanian Krishnan and Brian Billups
Biomolecules 2023, 13(5), 819; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13050819 - 11 May 2023
Cited by 3 | Viewed by 1851
Abstract
D-serine is an important signalling molecule, which activates N-methyl D-aspartate receptors (NMDARs) in conjunction with its fellow co-agonist, the neurotransmitter glutamate. Despite its involvement in plasticity and memory related to excitatory synapses, its cellular source and sink remain a question. We hypothesise that [...] Read more.
D-serine is an important signalling molecule, which activates N-methyl D-aspartate receptors (NMDARs) in conjunction with its fellow co-agonist, the neurotransmitter glutamate. Despite its involvement in plasticity and memory related to excitatory synapses, its cellular source and sink remain a question. We hypothesise that astrocytes, a type of glial cell that surrounds synapses, are likely candidates to control the extracellular concentration of D-Serine by removing it from the synaptic space. Using in situ patch clamp recordings and pharmacological manipulation of astrocytes in the CA1 region of the mouse hippocampal brain slices, we investigated the transport of D-serine across the plasma membrane. We observed the D-serine-induced transport-associated currents upon puff-application of 10 mM D-serine on astrocytes. Further, O-benzyl-L-serine and trans-4-hydroxy-proline, known substrate inhibitors of the alanine serine cysteine transporters (ASCT), reduced D-serine uptake. These results indicate that ASCT is a central mediator of astrocytic D-serine transport and plays a role in regulating its synaptic concentration by sequestration into astrocytes. Similar results were observed in astrocytes of the somatosensory cortex and Bergmann glia in the cerebellum, indicative of a general mechanism expressed across a range of brain areas. This removal of synaptic D-serine and its subsequent metabolic degradation are expected to reduce its extracellular availability, influencing NMDAR activation and NMDAR-dependent synaptic plasticity. Full article
(This article belongs to the Special Issue Alterations in D-amino Acid Metabolism in Psychiatric and Neurological Disorders)
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Review

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12 pages, 10063 KiB  
Review
Biochemical Properties and Physiological Functions of pLG72: Twenty Years of Investigations
by Giulia Murtas, Loredano Pollegioni, Gianluca Molla and Silvia Sacchi
Biomolecules 2022, 12(6), 858; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12060858 - 20 Jun 2022
Cited by 3 | Viewed by 2067
Abstract
In 2002, the novel human gene G72 was associated with schizophrenia susceptibility. This gene encodes a small protein of 153 amino acids, named pLG72, which represents a rare case of primate-specific protein. In particular, the rs2391191 single nucleotide polymorphism (resulting in in the [...] Read more.
In 2002, the novel human gene G72 was associated with schizophrenia susceptibility. This gene encodes a small protein of 153 amino acids, named pLG72, which represents a rare case of primate-specific protein. In particular, the rs2391191 single nucleotide polymorphism (resulting in in the R30K substitution) was robustly associated to schizophrenia and bipolar disorder. In this review, we aim to summarize the results of 20 years of biochemical investigations on pLG72. The main known role of pLG72 is related to its ability to bind and inactivate the flavoenzyme d-amino acid oxidase, i.e., the enzyme that controls the catabolism of d-serine, the main NMDA receptor coagonist in the brain. pLG72 was proposed to target the cytosolic form of d-amino acid oxidase for degradation, preserving d-serine and protecting the cell from oxidative stress generated by hydrogen peroxide produced by the flavoenzyme reaction. Anyway, pLG72 seems to play additional roles, such as affecting mitochondrial functions. The level of pLG72 in the human body is still a controversial issue because of its low expression and challenging detection. Anyway, the intriguing hypothesis that pLG72 level in blood could represent a suitable marker of Alzheimer’s disease progression (a suggestion not sufficiently established yet) merits further investigations. Full article
(This article belongs to the Special Issue Alterations in D-amino Acid Metabolism in Psychiatric and Neurological Disorders)
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Other

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51 pages, 2352 KiB  
Systematic Review
Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics
by Andrea de Bartolomeis, Licia Vellucci, Mark C. Austin, Giuseppe De Simone and Annarita Barone
Biomolecules 2022, 12(7), 909; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12070909 - 29 Jun 2022
Cited by 15 | Viewed by 3589
Abstract
Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical–subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently [...] Read more.
Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical–subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently available therapies. D-amino acids, acting as N-methyl-D-aspartate receptor (NMDAR) modulators, have emerged in the last few years as a potential augmentation strategy in those cases of schizophrenia that do not respond well to antipsychotics, a condition defined as treatment-resistant schizophrenia (TRS), affecting almost 30–40% of patients, and characterized by serious cognitive deficits and functional impairment. In the present systematic review, we address with a direct and reverse translational perspective the efficacy of D-amino acids, including D-serine, D-aspartate, and D-alanine, in poor responders. The impact of these molecules on the synaptic architecture is also considered in the light of dendritic spine changes reported in schizophrenia and antipsychotics’ effect on postsynaptic density proteins. Moreover, we describe compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes. Finally, other drugs acting at NMDAR and proxy of D-amino acids function, such as D-cycloserine, sarcosine, and glycine, are considered in the light of the clinical burden of TRS, together with other emerging molecules. Full article
(This article belongs to the Special Issue Alterations in D-amino Acid Metabolism in Psychiatric and Neurological Disorders)
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