Prenatal expression of d-aspartate oxidase causes early cerebral d-aspartate depletion and influences brain morphology and cognitive functions at adulthood

Rosa, Arianna De; Mastrostefano, Francesca; Maio, Anna; Nuzzo, Tommaso; Saitoh, Yasuaki; Katane, Masumi; Isidori, Andrea M.; Caputo, Viviana; Marotta, Pina; Falco, Geppino; Stefano, Maria Egle De; Homma, Hiroshi; Usiello, Alessandro; Errico, Francesco

doi:10.1007/s00726-020-02839-y

Cited by 16 publications

(32 citation statements)

References 54 publications

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“…Moreover, D-Asp has also been shown to activate mGluR5-dependent transmission [28]. Remarkably, in mammalian brain D-Asp display a peculiar time-dependent occurrence, since it is highly abundant only at embryonic stages of life [29][30][31]. D-Ser is synthesized de novo by serine racemase (SR) [32,33], while the metabolic pathway responsible for D-Asp biosynthesis has not yet been clearly defined [34][35][36].…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Dysfunctional d-aspartate metabolism in BTBR mouse model of idiopathic autism

Nuzzo

Sekine

Punzo

et al. 2020

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Dysfunctional d-aspartate metabolism in BTBR mouse model of idiopathic autism

Nuzzo

Sekine

Punzo

et al. 2020

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…Free D-Asp in mammals was first discovered in rats and humans at the end of the 1980s [20]. This atypical amino acid has been found in the CNS of rats [20,21], mice [22][23][24], and humans [10,13,25]. Although amino acids are predominantly present in mammalian tissues in the L-form, D-Asp content in the human embryonic prefrontal cortex (PFC) exceeds even the amount of its enantiomer, L-Asp (mean values: D-Asp = 0.036 µmol/g, L-Asp = 0.21 µmol/g), while the levels of this D-amino acid are drastically reduced at adulthood (0.008 µmol/g) [9,10,25,26].…”

Section: Free D-aspartate Distribution In the Mammalian Central Nervomentioning

confidence: 99%

“…Interestingly, the extraordinary gestational abundance of the D-Asp/total Asp ratio significantly differs between the human and rodent nervous systems. Indeed, a recent study in mice showed that D-Asp levels never reach as high as 12% of total embryonic Asp [22], whereas in the human PFC homogenates at gestational week 14, its relative abundance is around 65% [10].…”

Section: Free D-aspartate Distribution In the Mammalian Central Nervomentioning

confidence: 99%

“…Notably, a recent study revealed a severe reduction of Ddo gene expression accompanied by an increase of D-Asp levels in the brain of BTBR mice, which is a widely accredited animal model of idiopathic autism [14]. Furthermore, in an attempt to understand the biological meaning of the elevated levels of D-Asp during brain development, a Ddo knock-in mouse model with complete depletion of this D-amino acid has been generated [22]. Interestingly, Ddo knock-in mice are viable, fertile, and have normal gross brain morphology in adult stage; however, they have paradoxically enhanced memory abilities as evaluated by the object recognition and MWM tests associated to an altered number of cortical parvalbumin-positive interneurons [22].…”

Section: Animal Models With Altered D-aspartate Metabolismmentioning

confidence: 99%

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New Evidence on the Role of D-Aspartate Metabolism in Regulating Brain and Endocrine System Physiology: From Preclinical Observations to Clinical Applications

Usiello

Fiore

Rosa

et al. 2020

IJMS

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The endogenous amino acids serine and aspartate occur at high concentrations in free D-form in mammalian organs, including the central nervous system and endocrine glands. D-serine (D-Ser) is largely localized in the forebrain structures throughout pre and postnatal life. Pharmacologically, D-Ser plays a functional role by acting as an endogenous coagonist at N-methyl-D-aspartate receptors (NMDARs). Less is known about the role of free D-aspartate (D-Asp) in mammals. Notably, D-Asp has a specific temporal pattern of occurrence. In fact, free D-Asp is abundant during prenatal life and decreases greatly after birth in concomitance with the postnatal onset of D-Asp oxidase expression, which is the only enzyme known to control endogenous levels of this molecule. Conversely, in the endocrine system, D-Asp concentrations enhance after birth during its functional development, thereby suggesting an involvement of the amino acid in the regulation of hormone biosynthesis. The substantial binding affinity for the NMDAR glutamate site has led us to investigate the in vivo implications of D-Asp on NMDAR-mediated responses. Herein we review the physiological function of free D-Asp and of its metabolizing enzyme in regulating the functions of the brain and of the neuroendocrine system based on recent genetic and pharmacological human and animal studies.

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“…D-Aspartate potentially affects glutamatergic neurotransmission by binding to NMDA receptors and may be involved in neurotoxicity [16], but the knockout of SR in mice only partially lowers brain D-aspartate [9]. On the other hand, depletion of D-aspartate in embryos of knock-in mice expressing the D-aspartate oxidase increases interneuron population density and improves memory performance in adulthood [17]. In this context, we cannot discard the possibility that D-aspartate is a neurotoxic by-product.…”

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confidence: 99%

Promiscuous enzymes generating d-amino acids in mammals: Why they may still surprise us?

Wolosker

Radzishevsky

2021

Biochemical Journal

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Promiscuous catalysis is a common property of enzymes, particularly those using pyridoxal 5′-phosphate as a cofactor. In a recent issue of this journal, Katane et al. Biochem. J. 477, 4221–4241 demonstrate the synthesis and accumulation of d-glutamate in mammalian cells by promiscuous catalysis mediated by a pyridoxal 5′-phosphate enzyme, the serine/threonine dehydratase-like (SDHL). The mechanism of SDHL resembles that of serine racemase, which synthesizes d-serine, a well-established signaling molecule in the mammalian brain. d-Glutamate is present in body fluids and is degraded by the d-glutamate cyclase at the mitochondria. This study demonstrates a biochemical pathway for d-glutamate synthesis in mammalian cells and advances our knowledge on this little-studied d-amino acid in mammals. d-Amino acids may still surprise us by their unique roles in biochemistry, intercellular signaling, and as potential biomarkers of disease.

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Prenatal expression of d-aspartate oxidase causes early cerebral d-aspartate depletion and influences brain morphology and cognitive functions at adulthood

Cited by 16 publications

References 54 publications

Dysfunctional d-aspartate metabolism in BTBR mouse model of idiopathic autism

Dysfunctional d-aspartate metabolism in BTBR mouse model of idiopathic autism

New Evidence on the Role of D-Aspartate Metabolism in Regulating Brain and Endocrine System Physiology: From Preclinical Observations to Clinical Applications

Promiscuous enzymes generating d-amino acids in mammals: Why they may still surprise us?

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