Biochemical Properties and Physiological Functions of pLG72: Twenty Years of Investigations

Abstract

In 2002, the novel human gene G72 was associated with schizophrenia susceptibility. This gene encodes a small protein of 153 amino acids, named pLG72, which represents a rare case of primate-specific protein. In particular, the rs2391191 single nucleotide polymorphism (resulting in in the R30K substitution) was robustly associated to schizophrenia and bipolar disorder. In this review, we aim to summarize the results of 20 years of biochemical investigations on pLG72. The main known role of pLG72 is related to its ability to bind and inactivate the flavoenzyme d-amino acid oxidase, i.e., the enzyme that controls the catabolism of d-serine, the main NMDA receptor coagonist in the brain. pLG72 was proposed to target the cytosolic form of d-amino acid oxidase for degradation, preserving d-serine and protecting the cell from oxidative stress generated by hydrogen peroxide produced by the flavoenzyme reaction. Anyway, pLG72 seems to play additional roles, such as affecting mitochondrial functions. The level of pLG72 in the human body is still a controversial issue because of its low expression and challenging detection. Anyway, the intriguing hypothesis that pLG72 level in blood could represent a suitable marker of Alzheimer’s disease progression (a suggestion not sufficiently established yet) merits further investigations.

On the regulation of human D‐aspartate oxidase

“…hDASPO interacts with pLG72, a process affecting the cellular level of the flavoenzyme. Considering that pLG72 is assumed to act as a negative chaperone of hDAAO, boosting its degradation (Murtas et al, 2022 ; Sacchi et al, 2016 ) and, consistently with the observed decrease in hDASPO cellular levels and half‐life when pLG72 is simultaneously expressed, we propose that pLG72 plays a similar role on hDASPO. Since the latter is an extremely active and efficient flavoenzyme (Molla et al, 2020 ), the presence of a significant amount of the substrate might produce an abnormal increase in the ROS species H 2 O 2 and, eventually, induce a stress condition.…”

“…Concerning regulation by protein interaction, hDAAO is specifically regulated by the binding of the small, primate‐specific protein pLG72; see Murtas et al ( 2022 ) for a recent review. Similarly, both the wild‐type protein and the pathological R30K variant bind hDASPO with micromolar affinity, yielding the formation of a ~114 kDa complex.…”

“…Here, combining in vitro and cellular studies, we addressed the issue of the hDASPO main isoform (hDASPO_341) regulation by post‐translational modifications (PTMs) and the binding of pLG72, the main known protein modulator of hDAAO (Murtas et al, 2022 ; Pollegioni, Piubelli, et al, 2018 ).…”

Decreased free D-aspartate levels in the blood serum of patients with schizophrenia

“…In agreement with the hypothesis of NMDAR hypofunction in SCZ ( 41 , 42 ), previous evidence indicates lower D-Ser levels in the serum and cerebrospinal fluid of patients with SCZ ( 43 – 56 ). Furthermore, genetic studies revealed an association between SCZ and serine racemase ( SR ), and D-amino acid oxidase ( DAAO ) genes ( 57 – 61 ), as well as G72 gene, encoding the main DAAO modulator, pLG72 ( 62 – 64 ). Moreover, both D-Ser supplementation and DAAO inhibition have shown beneficial effects in modulating mismatch negativity response, cognition and extrapyramidal side-effects linked to antipsychotic treatment in SCZ patients ( 65 – 71 ).…”