Deficit schizophrenia and its features are associated with PON1 Q192R genotypes and lowered paraoxonase 1 (PON1) enzymatic activity: effects on bacterial translocation

Abstract

Background. Primary deficit schizophrenia (DS) is characterized by enduring negative symptoms and represents a qualitatively different disease entity with respect to non-deficit schizophrenia (NDS). No studies investigated the association between the enzyme paraoxonase 1 (PON1) and DS and its phenomenology. Methods. In this case-control study, Thai women and men, aged 18 to 65 years, were divided in DS (n = 40) and NDS (n = 40) and were compared to controls (n = 40). PON1 activities against 4-(chloromethyl)phenyl acetate (CMPA) and phenylacetate were determined. Moreover, subjects were genotyped for their PON1 Q192R polymorphism and immunoglobulin A (IgA) levels responses directed to Gram-negative bacteria were measured. Results. DS is significantly associated with the QQ genotype and the Q allele as compared with NDS and controls. PON1 activities are significantly and inversely associated with negative symptoms, formal thought disorders, psychomotor retardation, excitation and DS. The presence of the Q allele is associated with increased IgA responses to Pseudomonas aeruginosa, Morganella morganii, and Pseudomonas putida as compared with RR carriers. Conclusions. The PON1 Q allele and lower PON1 activities especially against CMPA are associated with DS, indicating lowered quorum quenching abilities as well as lowered defenses against lipoperoxidation and immune activation. It is suggested that lowered PON1 activity in DS constitutes an impairment in the innate immune system which together with lowered natural IgM may cause lower immune regulation thereby predisposing toward greater neurotoxic effects of immune-inflammatory, oxidative and nitrosative pathways and Gram-negative microbiota.

Construction of a Neuro-Immune-Cognitive Pathway-Phenotype Underpinning the Phenome of Deficit Schizophrenia

“…As such, there is theoretical evidence to bring immune markers and neurocognitive impairments together in constructs to be modeled by PLS or SIMCA. Of course, it would have been even more interesting if we had measured other neuro-immune biomarkers that play a key role in deficit schizophrenia including deficits in innate immunity such as lowered natural IgM responses and lowered paraoxonase 1 activities, which together increase vulnerability to immune activation, oxidative stress, bacterial load and inflammation [4,31]. Another immune and oxidative stressassociated pathway that is activated in deficit schizophrenia is the tryptophan catabolite (TRYCAT) pathway with increased levels of neurotoxic TRYCATS, including xanthurenic acid, picolinic acid and 3-OH-kunerenine [18,19].…”

How to Construct a Bottom-Up Nomothetic Network Model and Disclose Novel Nosological Classes by Integrating Risk Resilience and Adverse Outcome Pathways with the Phenome of Schizophrenia

“…We performed clustering analysis to classify the patien latent variable scores reflecting causome, AOPs, and phenom mean, K-median, and Forgy's method using SPSS 25 [14].…”

“…There were significant indirect effects of (a) zonulin (t = 2.31, p = 0.021), PONgenozyme (t = 2.39, p = 0.017) and natural IgM (t = 4.91, p < 0.001) on the symptomatome, all mediated by AOPs; (b) zonulin on the phenomenome mediated by the path from AOP immunoturbidimetric procedure with a kit purchased from Abbott (Chica Architect, model C8000, Abbott (Chicago, IL, USA). Total PON1 status, na genotype in an additive model and PON1 chloromethyl phenol aceta (PONgenozym) were analyzed using phenyl acetate (Sigma, St. Louis, MO condition and CMPA (Sigma, St. Louis, MO, USA) as substrates [14].…”

“…to estimate cause-effect path models, thereby combining principal component analysis to construct latent vectors coupled with multiple regression analysis. Hence, this study aims to explain how (a) to construct a reliable and replicable nomothetic network of schizophrenia based on a theoretical model that was pre-specified based on our previous knowledge [1][2][3][4][5][9][10][11][12][13][14] (Figure 1) using feature sets extracted from RR, AOP, and phenome data; and (b) to discover a new classification of schizophrenia based on the same feature sets. Toward this end, we will explain how to use PLS path modeling as a bottom-up, pattern recognition approach to construct a novel nomothetic network, which reflects the direct effects of the RR on the AOPs, and the direct and mediated effects of both RR and AOPs on the different features of the phenome.…”

“…Moreover, in deficit schizophrenia, additional impairments are detected in natural IgM-mediated autoimmune responses to oxidative specific epitopes (OSEs), which have strong anti-inflammatory, antioxidant, and antibacterial effects [ 9 ]. Finally, deficit schizophrenia is associated with the total paraoxonase 1 (PON1) status, namely a higher frequency of the Q allele and QQ genotype of the Q192R polymorphism in association with lowered activity of PON1 paraoxonase, an enzyme with anti-oxidative, anti-inflammatory, and antibacterial properties [ 14 ].…”