Oxidative stress, rRNA genes, and antioxidant enzymes in pathogenesis of schizophrenia and autism: Modeling and clinical recommendations

Abstract

Ribosomal genes (RG), or rRNA genes, in eukaryotic genomes are represented by numerous tan dem repeats, of which only a portion are transcriptionally active. The number of active copies is a constant feature of genome genome determining the cell's ability for the rapid synthesis of proteins needed to over come the effects of stress. A low number of active RG copies leads to reduced stress resistance and elevated risk of multifactorial diseases (MFDs). Oxidative stress (OS) in the brain cells is believed to be involved in the pathogenesis of infantile autism (IA) and schizophrenia, that is, MFDs with severe genetic predisposition. With autism, OS markers are detected almost in every study, while with schizophrenia the OS data are con tradictory. In a sample of patients with schizophrenia, we previously found a significantly higher quantity of active RG copies than in the population on average. In this work, we have determined the number of active RG copies in a sample of patients with IA (n = 51) and revealed a significantly lower mean value than in a healthy population. A novel mathematical model of the dynamic pattern of OS has been proposed. This model was implemented as a system of ordinary differential equations and assumes the induction of antioxi dant protection enzymes being mediated by reactive oxygen species (ROS), with a subsequent decrease in the intracellular concentration of ROS. The rate of synthesis of antioxidant protection enzymes is limited by the ribosome synthesis rate, which depends on the number of active RG copies. Analysis of the model showed that the system always approaches a single point of stable equilibrium via the mechanism of damping oscilla tions, which to a certain extent resembles the dynamics of "predator-prey" interaction in the Lotka-Volterra model. The equilibrium ROS level inversely depends on the number of active RG copies. Our study allows us to explain the inconsistency of clinical data when detecting OS in IA and schizophrenia, suggesting a novel criterion for differential cytogenetic diagnostics of schizophrenia and IA, and to assume that antioxidant therapy should be effective only for children with a low number of active RG copies.

Delineating inflammatory bowel disease through transcriptomic studies: current review of progress and evidence

“… 38 Variations in rRNA genes and its expression level has been reported to be associated with carcinogenesis, pathogenesis of schizophrenia and autism as well as in hearing loss. 39 40…”