γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS), regulates neuronal excitability, synaptic plasticity, and oscillatory activity essential for cognition, emotion, and behavior. Disruptions in GABAergic signaling are increasingly recognized as key contributors to a range of neurodevelopmental disorders (NDDs), including schizophrenia (SZ), autism spectrum disorder (ASD), major depressive disorder (MDD), bipolar disorder (BD), and intellectual disability (ID). In this review, we analyze the data available from the literature concerning the components of the GABA pathway. We describe the main steps of GABA metabolism, including GABA synthesis and release, GABA receptors neurotransmission, GABA reuptake and catabolism, and evaluate their involvement in the pathogenesis of neurodevelopmental disorders. We suggest the possibility of existence of so far undescribed mechanisms which maintain the concentrations of GABA at a relatively physiological level when the function of glutamic acid decarboxylases is compromised by mutations. Searching for these mechanisms could be important for better understanding neurodevelopment and could give a clue for future searches for new therapeutic approaches for treating or alleviating the symptoms of BD and SZ. We also argue that the metabolic stage of the GABA pathway has only a minor direct effect on GABA signaling and rather causes clinical effects due to accumulation of neurotoxic byproducts.

Schizophrenia (SZ) is a common psychiatric neurodevelopmental disorder with a complex genetic architecture. Genome-wide association studies indicate the involvement of several transcription factors, including ASCL1, in the pathogenesis of SZ. We aimed to identify ASCL1-dependent cellular and molecular mechanisms associated with SZ. We used Capture-C, CRISPR/Cas9 systems and RNA-seq analysis to confirm the involvement of ASCL1 in SZ-associated pathogenesis, establish a mutant SH-SY5Y line with a functional ASCL1 knockout (ASCL1-del) and elucidate differentially expressed genes that may underlie ASCL1-dependent pathogenic mechanisms. Capture-C confirmed the spatial interaction of the ASCL1 promoter with SZ-associated loci. Transcriptome analysis showed that ASCL1 regulation may be through a negative feedback mechanism. ASCL1 dysfunction affects the expression of genes associated with the pathogenesis of SZ, as well as bipolar and depressive disorders. Genes differentially expressed in ASCL1-del are involved in cell mitosis, neuronal projection, neuropeptide signaling, and the formation of intercellular contacts, including the synapse. After retinoic acid (RA)-induced differentiation, ASCL1 activity is restricted to a small subset of genes involved in neuroplasticity. These data suggest that ASCL1 dysfunction promotes SZ development predominantly before the onset of neuronal differentiation by slowing cell proliferation and impeding the formation of neuronal signatures.

Schizophrenia is a severe mental illness, the etiology and pathogenesis of which are significantly contributed by hereditary factors. Genome-wide association analysis shows that the majority of genetic variants associated with a high risk of schizophrenia are located in regulatory regions of genes. In this brief review, data on the overall structure of the major regulatory regions of genes are summarized. The main focus is on enhancers, which are regions of the genome that enhance gene activity. The participation of transcription factors interacting with gene regulatory regions in various molecular and cellular processes, the disruption of which is associated with the pathogenesis of schizophrenia, is discussed in detail.

The SLC6A1 gene encodes the GAT-1 transporter, which mediates the reuptake of GABA in the central nervous system (CNS). Missense variants in this gene are associated with the development of neuropsychiatric disorders, including schizophrenia. Although in vitro assays demonstrate a loss of transport activity, they do not elucidate how specific amino acid substitutions disrupt local interactions within the protein. To delineate the structural consequences of these mutations, we analyzed the inward-open apo-state of human GAT-1 (PDB: 7Y7V) using microsecond-scale molecular dynamics (MD) simulations. This study compares the wild-type transporter with mutant forms, including the schizophrenia-associated variants R211C and A305T, alongside the A346S variant selected via deep learning-based pathogenicity predictors. The results demonstrate that these mutations do not globally destabilize the protein structure; rather, they induce specific rearrangements within local contact networks. The R211C substitution abolishes a hydrogen bond at the interface of extracellular loop 2 (EL2) and transmembrane helix 4 (TM4). A305T alters the TM1–TM6 interface adjacent to the sodium ion-binding site, and A346S strengthens TM1/TM6–EL4 interactions. The identified structural shifts suggest how pathogenic mutations remodel the GAT-1 interaction network and alter its conformational dynamics. These findings provide a foundation for subsequent molecular docking aimed at drug repurposing and for comprehensive MD modeling of the complete GAT-1 transport cycle.

Жизнедеятельность клетки в значительной степени зависит от точной регуляции экспрессии генов. Одним из механизмов такой регуляции является формирование нуклеиновыми кислотами вторичных структур, среди которых особое место занимают гуаниновые квадруплексы (G-квадруплексы, или G4). G-квадруплексы – динамические структуры, стабильность которых определяется их размером, ионным составом и природой образующих их нуклеиновых кислот, и регулируется разнообразными белковыми факторами. Гуаниновые квадруплексы играют важную роль в регуляции многих процессов, происходящих на ДНК и РНК, – от поддержания гомеостаза теломер до определения сайта посадки рибосомы на мРНК. Благодаря этому G-квадруплексы считаются перспективной мишенью для противоопухолевой терапии, а их детальное изучение представляет важную задачу современной биологии. В обзоре рассмотрена структура и термодинамические свойства G-квадруплексов, их биологические функции, а также их взаимодействие с некоторым ядерными белками.