Blood levels of D-aspartate oxidase, D-amino acid oxidase, serine racemase, and pLG72 are influenced by diagnoses of schizophrenia and autism spectrum disorder

Abstract Free D-serine (D-Ser) and D-aspartate (D-Asp) are increasingly recognized as key modulators of glutamatergic NMDA receptor-dependent neurotransmission, whose dysfunction has been implicated in neuropsychiatric conditions, including schizophrenia (SCZ) and autism spectrum disorder (ASD). The metabolism of these D-amino acids is tightly regulated by specific enzymes: serine racemase (SR) for D-Ser synthesis and degradation, and D-amino acid oxidase (DAAO) and D-aspartate oxidase (DASPO) for D-Ser and D-Asp degradation, respectively. The primate-specific protein pLG72 further modulates the activity of DAAO and DASPO. In this multicenter study, we employed a mass spectrometry (MS)-based approach to quantify SR, DAAO, DASPO, and pLG72 levels in serum samples from SCZ and ASD patients, along with matched non-psychiatric controls. Enzymatic activity and D-amino acid serum concentrations were also assessed. We identified distinct, disorder-specific alterations in these proteins. In SCZ patients, SR protein levels were elevated despite unchanged activity, while DAAO and pLG72 levels were decreased. Conversely, increased DASPO levels were associated with reduced D-Asp, indicating enhanced catabolism of this endogenous NMDA receptor ligand in SCZ. ASD patients exhibited elevated DAAO and DASPO, with reduced SR levels. Notably, positive correlations between pLG72 and both DAAO and DASPO flavoenzymes were observed in both disorders. These findings highlight the potential of D-amino acid metabolism-related enzymes as biomarkers for SCZ and ASD and provide new insights for future diagnostic and mechanistic investigations in neurodevelopmental disorders.