The amino acid D-aspartate (D-Asp) transiently occurs in the mammalian brain since it is abundant during prenatal life but strongly decreases in adulthood due to postnatal expression/activity of the catabolic enzyme D-aspartate oxidase (DASPO or DDO) [1-4]. Beyond its intracellular occurrence, D-Asp is also present at the extracellular level where it acts as an endogenous agonist at NMDA and mGlu5 receptors [5-8]. Based on early abundance of cerebral D-Asp and on the large bulk of evidence suggesting a developmental dysfunction of glutamatergic transmission in schizophrenia (SCZ) and autism spectrum disorders (ASD), we postulated an involvement of an altered D-Asp metabolism in such psychiatric diseases. Consistent with this assumption, we recently documented substantial changes in D-Asp levels within: i) prefrontal cortex of two cohorts of SCZ patients [9,10] and ii) prefrontal cortex and hippocampus of an idiopathic mouse model of ASD [11]. Remarkably, we identified (preliminary data) the first patient with a Ddo gene duplication showing severe intellectual disability (ID) and ASD symptoms. Moreover, our recent nuclear magnetic resonance and mass spectrometry analysis in transgenic Ddo overexpressing mice showed that cerebral D-Asp deficiency dramatically influences the occurrence of molecules involved in brain energy metabolism and development [11]. Considering that D-Asp synthetic pathway is still puzzling, DASPO is the only known enzyme able to control D-Asp endogenous levels by catalysing its degradation: we recently solved the 3D structure of human DASPO and shed light on its structure-function relationships [12].
The aim of this project, proposed by 5 teams covering different and complementary expertise areas, is to evaluate the processes involved in the modulation of D-Asp metabolism by DASPO under physiological and pathological conditions. We plan to: i) design, identify and characterize novel DASPO inhibitors; ii) identify the role of DASPO isoforms and their subcellular localization, and the DASPO interactome; iii) clarify the effect of Ddo gene dosage on cell survival and proliferation, NMDA receptor-dependent synaptic transmission and plasticity, and ASD-related phenotypes; iv) evaluate the blood D-Asp levels in ASD patients; v) perform neuroanatomical studies and in vivo imaging analysis; vi) evaluate the in vivo effect of modulation of DASPO activity.
To accomplish this project, we will use: recombinant proteins and libraries of chemical compounds; mice models with different Ddo gene dosage as well idiopathic models of ASD; selected cell lines ectopically expressing DASPO and blood cells from a case of Ddo gene duplication; blood samples from ASD patients.
The expected results might allow the identification and characterization of mechanisms controlling D-Asp metabolism and thus provide a translational significance to DASPO, linking its deregulations to the emergence of neurodevelopmental disorders, including SCZ, ASD, and ID.
The aim of this project, proposed by 5 teams covering different and complementary expertise areas, is to evaluate the processes involved in the modulation of D-Asp metabolism by DASPO under physiological and pathological conditions. We plan to: i) design, identify and characterize novel DASPO inhibitors; ii) identify the role of DASPO isoforms and their subcellular localization, and the DASPO interactome; iii) clarify the effect of Ddo gene dosage on cell survival and proliferation, NMDA receptor-dependent synaptic transmission and plasticity, and ASD-related phenotypes; iv) evaluate the blood D-Asp levels in ASD patients; v) perform neuroanatomical studies and in vivo imaging analysis; vi) evaluate the in vivo effect of modulation of DASPO activity.
To accomplish this project, we will use: recombinant proteins and libraries of chemical compounds; mice models with different Ddo gene dosage as well idiopathic models of ASD; selected cell lines ectopically expressing DASPO and blood cells from a case of Ddo gene duplication; blood samples from ASD patients.
The expected results might allow the identification and characterization of mechanisms controlling D-Asp metabolism and thus provide a translational significance to DASPO, linking its deregulations to the emergence of neurodevelopmental disorders, including SCZ, ASD, and ID.