Effects of Psychotropic Drugs on Ribosomal Genes and Protein Synthesis

Liu, Zoe; Truong, Trang T. T.; Bortolasci, Chiara C.; Spolding, Briana; Panizzutti, Bruna; Swinton, Courtney; Kim, Jee Hyun; Kidnapillai, Srisaiyini; Richardson, Mark F.; Gray, Laura J.; Dean, Olivia; McGee, Sean L.; Berk, Michael; Walder, Ken

doi:10.3390/ijms23137180

Cited by 10 publications

(4 citation statements)

References 64 publications

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“…For ribosomes, increased total protein levels and protein synthesis were reported in induced pluripotent stem cells derived from schizophrenia patients versus healthy controls [48]. We also found antipsychotic drugs reduced overall expression of ribosomal genes and protein synthesis in neuronal-like cells [49]. The validity of this finding is suggested by research showing that N-acetylcysteine which ameliorates redox dysfunction may have benefits in schizophrenia, especially negative symptoms [50].…”

Section: Discussionsupporting

confidence: 52%

Network-based drug repurposing for schizophrenia

Truong,

Liu,

Panizzutti

et al. 2024

Neuropsychopharmacol.

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Despite recent progress, the challenges in drug discovery for schizophrenia persist. However, computational drug repurposing has gained popularity as it leverages the wealth of expanding biomedical databases. Network analyses provide a comprehensive understanding of transcription factor (TF) regulatory effects through gene regulatory networks, which capture the interactions between TFs and target genes by integrating various lines of evidence. Using the PANDA algorithm, we examined the topological variances in TF-gene regulatory networks between individuals with schizophrenia and healthy controls. This algorithm incorporates binding motifs, protein interactions, and gene co-expression data. To identify these differences, we subtracted the edge weights of the healthy control network from those of the schizophrenia network. The resulting differential network was then analysed using the CLUEreg tool in the GRAND database. This tool employs differential network signatures to identify drugs that potentially target the gene signature associated with the disease. Our analysis utilised a large RNA-seq dataset comprising 532 post-mortem brain samples from the CommonMind project. We constructed co-expression gene regulatory networks for both schizophrenia cases and healthy control subjects, incorporating 15,831 genes and 413 overlapping TFs. Through drug repurposing, we identified 18 promising candidates for repurposing as potential treatments for schizophrenia. The analysis of TF-gene regulatory networks revealed that the TFs in schizophrenia predominantly regulate pathways associated with energy metabolism, immune response, cell adhesion, and thyroid hormone signalling. These pathways represent significant targets for therapeutic intervention. The identified drug repurposing candidates likely act through TF-targeted pathways. These promising candidates, particularly those with preclinical evidence such as rimonabant and kaempferol, warrant further investigation into their potential mechanisms of action and efficacy in alleviating the symptoms of schizophrenia.

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Section: Discussionsupporting

confidence: 52%

Network-based drug repurposing for schizophrenia

Truong,

Liu,

Panizzutti

et al. 2024

Neuropsychopharmacol.

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“…GO keywords related to cellular communication and regulation were repeated in treatment effectiveness and resistance comparisons, reflecting the major mechanism of drug action (99). Notably, pathway and network analyses revealed a strong correlation between DMRs associated with an effective antipsychotic response and genes implicated in the ribosome pathway, providing more evidence to support the hypothesis that treatment efficacy may be influenced by epigenetic modulation of ribosome-related genes (100). Interestingly, HDAC proteins were ranked top among resistance DMR proteins, suggesting their potential role in treatment resistance.…”

Section: Discussionmentioning

confidence: 84%

Methylome-wide and meQTL analysis helps to distinguish treatment response from non-response and pathogenesis markers in schizophrenia

Polakkattil,

Vellichirammal,

Nair

et al. 2024

Front. Psychiatry

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Schizophrenia is a complex condition with entwined genetic and epigenetic risk factors, posing a challenge to disentangle the intermixed pathological and therapeutic epigenetic signatures. To resolve this, we performed 850K methylome-wide and 700K genome-wide studies on the same set of schizophrenia patients by stratifying them into responders, non-responders, and drug-naïve patients. The key genes that signified the response were followed up using real-time gene expression studies to understand the effect of antipsychotics at the gene transcription level. The study primarily implicates hypermethylation in therapeutic response and hypomethylation in the drug-non-responsive state. Several differentially methylated sites and regions colocalized with the schizophrenia genome-wide association study (GWAS) risk genes and variants, supporting the convoluted gene–environment association. Gene ontology and protein–protein interaction (PPI) network analyses revealed distinct patterns that differentiated the treatment response from drug resistance. The study highlights the strong involvement of several processes related to nervous system development, cell adhesion, and signaling in the antipsychotic response. The ability of antipsychotic medications to alter the pathology by modulating gene expression or methylation patterns is evident from the general increase in the gene expression of response markers and histone modifiers and the decrease in class II human leukocyte antigen (HLA) genes following treatment with varying concentrations of medications like clozapine, olanzapine, risperidone, and haloperidol. The study indicates a directional overlap of methylation markers between pathogenesis and therapeutic response, thereby suggesting a careful distinction of methylation markers of pathogenesis from treatment response. In addition, there is a need to understand the trade-off between genetic and epigenetic observations. It is suggested that methylomic changes brought about by drugs need careful evaluation for their positive effects on pathogenesis, course of disease progression, symptom severity, side effects, and refractoriness.

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“…The small subunit of the ribosome is anchored to the mRNA so that a set of three nucleotides (a codon) can be presented to a specific tRNA at the amino-acyl site (A site) that carries the amino acid. The large subunit of the ribosome links each amino acid to synthesize the polypeptide chain at the peptide-base site (the P site), while the empty tRNA is ejected from the ribosome at the exit site (the E site) ( Liu et al, 2022 ). In our study, the 44 DMPs with both Kcr and Khib modifications are related to the ribosome pathway, which is involved in the two key components of ribosomes (40S and 60 subunits).…”

Section: Discussionmentioning

confidence: 99%

Qualitative lysine crotonylation and 2-hydroxyisobutyrylation analysis in the ovarian tissue proteome of piglets

Yang

et al. 2023

Front. Cell Dev. Biol.

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Ovarian function influences diverse aspects of fertility and reproductive lifespan by regulating oocyte supply and hormone secretion. Lysine crotonylation (Kcr) and lysine 2-hydroxyisobutyryllysine (Khib) are newly identified post-translational modifications and function as regulators of transactivation in mammals. In this study, we investigated protein post-translational Kcr and 2-hydroxyisobutyrylation in the ovarian tissues of piglets. A total of 653 overlapping proteins among differentially modified proteins were identified for both crotonylation and 2-hydroxyisobutyrylation. Gene Ontology enrichment analysis indicated that 653 DMPs were significantly enriched in nucleosome organization, chromatin assembly, DNA packaging, peptide biosynthetic process and peptide metabolic process. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed enrichment in proteasome, ribosome, fatty acid elongation, pyruvate metabolism and pentose phosphate pathway. Fifteen DMPs were identified in the proteasome pathway, of which PSMC6 and PSMB7 were the core proteins. In addition, the significant changes in Kcr and Khib in the complex subunits of the proteasome may be involved in cell cycle processes during oocyte development. Forty-four DMPs with both Kcr and Khib modifications were related to the ribosome pathway. The regulated ribosome pathway may indicate that Kcr and Khib comodified proteins participate in protein synthesis during oocyte development. Western blot and immunofluorescence staining results supported the reliability of the sequencing results. Our results may provide a valuable resource to help illuminate the roles of Kcr and Khib in ovarian development and may serve as new tools to better control diseases.

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Effects of Psychotropic Drugs on Ribosomal Genes and Protein Synthesis

Cited by 10 publications

References 64 publications

Network-based drug repurposing for schizophrenia

Network-based drug repurposing for schizophrenia

Methylome-wide and meQTL analysis helps to distinguish treatment response from non-response and pathogenesis markers in schizophrenia

Qualitative lysine crotonylation and 2-hydroxyisobutyrylation analysis in the ovarian tissue proteome of piglets

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