1,720,976 research outputs found
A D-Amino Acid Oxidase-based microbiosensor for D-Serine detection in the central nervous system.
No full textMolecular basis of schizophrenia: functional investigation of human D-amino acid oxidase-pLG72 interaction.
No full textCharacterization of D-Amino Acid Oxidase Microbiosensor for D-Serina detection in the central nervous system.
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d-Aspartate: An endogenous NMDA receptor agonist enriched in the developing brain with potential involvement in schizophrenia
No full textFree d-aspartate and d-serine occur at substantial levels in the mammalian brain. d-Serine is a physiological endogenous co-agonist for synaptic N-Methyl d-Aspartate (NMDA) receptors (NMDARs), and is involved in the pathophysiology of schizophrenia. Much less is known about the biological meaning of d-aspartate. d-Aspartate is present at high levels in the embryo brain and strongly decreases at post-natal phases. Temporal reduction of d-aspartate levels depends on the post-natal onset of d-aspartate oxidase (DDO), an enzyme able to selectively catabolize this d-amino acid. Pharmacological evidence indicates that d-aspartate binds to and activates NMDARs. Characterization of genetic and pharmacological mouse models with abnormally higher levels of d-aspartate has evidenced that increased d-aspartate enhances hippocampal NMDAR-dependent synaptic plasticity, dendritic morphology and spatial memory. In line with the hypothesis of a hypofunction of NMDARs in the pathogenesis of schizophrenia, it has been shown that increased d-aspartate levels also improve brain connectivity, produce corticostriatal adaptations resembling those observed after chronic haloperidol treatment, and protects against prepulse inhibition deficits and abnormal circuits activation induced by psychotomimetic drugs. In healthy humans, genetic variation predicting reduced expression of DDO in post-mortem prefrontal cortex is associated with greater prefrontal gray matter and activity during working memory. On the other side, evaluation of d-aspartate content in post-mortem patients with schizophrenia has shown a significant reduction of this d-amino acid in the prefrontal cortex and striatum. Generation of mouse models with reduced embryonic levels of d-aspartate may disclose unprecedented role for d-aspartate in developmental brain processes associated with vulnerability to psychotic-like symptoms
Characterization of a D-amino acid oxidase microbiosensor for D-serine detection in the central nervous system.
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pLG72 modulates intracellular D-serine levels through its interaction with D-amino acid oxidase - Effect on schizophrenia susceptibility
Full text linkHuman genes coding for pLG72 and d-amino acid oxidase have recently been linked to the onset of schizophrenia. pLG72 was proposed as an activator of the human FAD-containing flavoprotein d-amino acid oxidase (hDAAO). In the brain this oxidizes d-serine, a potent activator of N-methyl-d-aspartate receptor. We have investigated the mechanistic regulation of hDAAO by pLG72. Immunohistochemical analyses revealed that hDAAO and pLG72 are both expressed in astrocytes of the human cortex, where they most likely interact, considering their partial overlapping subcellular distribution and their coimmunoprecipitation. We demonstrated that the specific in vitro interaction of the two proteins yields a complex composed of 2 hDAAO homodimers and 2 pLG72 molecules. Binding of pLG72 did not affect the kinetic properties and FAD binding ability of hDAAO; instead, a time-dependent loss of hDAAO activity in the presence of an excess of pLG72 was found. The binding affects the tertiary structure of hDAAO, altering the amount of the active form. We finally demonstrated that overexpression of hDAAO in glioblastoma cells decreases the levels of d-serine, an effect that is null when pLG72 is coexpressed. These data indicate that pLG72 acts as a negative effector of hDAAO. Therefore, a decrease in the synaptic concentration of d-serine as the result of an anomalous increase in hDAAO activity related to hypoexpression of pLG72 may represent a molecular mechanism by which hDAAO and pLG72 are involved in schizophrenia susceptibility
Molecular basis of schizophrenia: functional investigation of human D-amino acid oxidase-pLG72 interaction.
No full textCharacterization of a yeast D-amino acid oxidase microbiosensor for D-serine detection in the central nervous system
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