Role of human DAAO in D-serine metabolism: new insight

D-amino acid oxidase (DAAO) is a peroxisomal flavoenzyme significantly enriched in the mammalian brain. It has been proposed to play (with serine racemase) an essential role in the catabolism of the “atypical” transmitter-like molecule D-serine, an allosteric activator of the NMDA receptor (NMDAr). Indeed, D-serine cellular concentration depends on the expression of active DAAO. Alterations in the enzyme functionality and/or in its cellular levels might contribute to D-serine signaling dysregulation and the associated NMDAr dysfunctions that occur in several pathological conditions, including neurodegenerative diseases and psychiatric disorders. Noteworthy, genetic evidences indicate that human DAAO (hDAAO) - and its negative regulator pLG72 – are related to schizophrenia. We demonstrated that newly synthesized hDAAO is active and interacts with its modulator in the cytosol being progressively inactivated. The largest part of hDAAO (a long lived protein) is degraded by the lysosomal system, while pLG72 (showing a rapid turnover) is mainly targeted to the proteasome: pLG72 binding destabilizes hDAAO and increases its degradation, likely playing a protective role against excessive D-serine depletion. Furthermore, we investigated the effect of SNPs in hDAAO potentially related to schizophrenia. D31H and R279A variants show an increased activity and their expression in U87 cells produced an higher decrease in D-serine cellular level than the wild-type counterpart. These substitutions could negatively affect the concentration in vivo of the neuromodulator and thus might be relevant for schizophrenia susceptibility.