Kommu Naga Mohan1,2*- 1Molecular Biology and Genetics Laboratory, Department of Biological Sciences, BITS Pilani Hyderabad Campus, Hyderabad, India
- 2Centre for Human Disease Research, BITS Pilani Hyderabad Campus, Hyderabad, India
Editorial on the Research Topic
New insights into investigating schizophrenia as a disorder of molecular pathways
Schizophrenia (SZ) is a complex disorder with ~1% incidence world-wide involving multiple risk factors such as chemical imbalance (e.g., neurotransmitters), infection (e.g., Toxoplasmosis), genetic susceptibility (e.g., three-fold familial risk with a first-degree relative) and epigenetic factors (e.g., high discordance rates in monozygotic twins) (Saxena et al., 2021). Many genetic and animal model studies have been carried out to date, but we are far from a complete understanding of the molecular/physiological basis for the onset and progression of SZ (e.g., Winship et al., 2019; Trubetskoy et al., 2022). Considerable efforts were also directed for targeting molecules suspected to be involved in positive and negative symptoms to develop antipsychotic drugs [reviewed in Corell (2020)]. However, these efforts have not yet provided completely curable or long-term solutions, mainly because of the lack of comprehensive understanding of the basic mechanisms, processes involving relapse, heterogeneity in the molecular abnormalities in patients, etc. (e.g., Farsi and Sheng, 2023).
Among the different lines of research involved in studying the basic mechanisms, the present article collection focuses on molecular pathways involved in SZ. In general, diverse sets of molecular pathways, broadly belong to four main categories of cellular signaling that are essential for various neurodevelopmental processes such as neuron cell survival, growth, death, neuron-to-neuron signaling, etc. (Table 1). Many of these pathways have been used to study the effects of some commonly used antipsychotic drugs, development of new generation of drugs and understand the basis of non-responsiveness in some cases. Nevertheless, as mentioned above, both basic and applied research are needed for better diagnosis and management of SZ.
Table 1. Selected pathways among the four broad categories of signaling processes and their relevance to schizophrenia.
Among the collection of articles under the Research Topic, one investigation involved the programmed cell death—associated genes dysregulated in SZ patients (Feng and Shen) who used transcriptome data from dorsolateral prefrontal cortex from the publicly available database containing 58 SZ patients and 175 controls as discovery group. The choice of cell death—related genes was also important because of the observations that the SZ patients showed accelerated aging effects with loss of gray and white matter (Cropley et al., 2017). Out of the 2,684 differentially expressed genes (DEGs) identified, 263 were among the genes linked to programmed cell death. Following extensive bioinformatic analysis including machine learning, protein-protein interactions and consensus cluster analysis, the authors identified 10 most differentially expressed genes (DPF2, ATG7, GSK3A, TFDP2, ACVR1, CX3CR1, AP4M1, DEPDC5, NRFA2, and IKBKB) that are also involved in different forms of cell death. The diagnostic value of expression states of these genes, when assessed by ROC curve analysis yielded an AUC of 0.91. These results were further confirmed using a validation dataset from BA10 (anterior prefrontal cortex) areas of 19 controls and 23 patients (AUC: 0.94). Further, when the proportions of immune cells were estimated using the ImmuneCellAI algorithm, the affected tissues showed significant differences in the levels of cytotoxic and natural killer cells. Finally, gene-drug interaction analysis identified aflatoxin B1, valproic acid (VPA), arsenic, benzo(a)pyrine, epigallocatechin gallate (EG) and nickel as interacting drugs. Together, the data from Feng and Shen suggest that: (1) At least a subset of patients can be diagnosed based on dysregulated states of the identified set of the 10 cell death—related genes and (2) Drugs such as VPA and EG may be useful for treatment of this subset. Of these, VPA is known to increase the levels of GABA, block voltage-gated ion channels and inhibit histone deacetylase (HDAC) activity (Ghodke-Puranik et al., 2013).
The second article in this Research Topic focused on perturbation of the levels of DNA methyltransferase 1, required for maintenance of DNA methylation an important epigenetic modification (Mohan and Chaillet, 2013). Singh et al. based their study on the observations that DNMT1 overexpression is a risk factor for SZ, epilepsy and bipolar disorders (Veldic et al., 2005; Zhu et al., 2012) and used genetically modified mouse embryonic stem cell line that overexpresses the enzyme. Interestingly, the same cell line can be made to turn off the Dnmt1 expression by treatment with doxycycline. Transcriptome analysis of the neurons produced by these cells under both doxycycline-treated and untreated conditions identified ~3,000 dysregulated genes for each category. Several of these genes were involved in neurodevelopmental processes, neurotransmission, synaptic function, extracellular signaling, cell–cell junctions, extracellular matrix interactions, DNA replication, DNA repair, translation machinery, etc. These genes were also subjected to transcript level changes in patients with any of the three disorders as well as autism spectrum disorder. This data provided evidence in support of the hypothesis that both loss as well as increased expression of DNMT1 as factors influencing abnormal behavior and that DNMT1 levels need to be maintained within a normal range for better outcomes (Mohan, 2022).
Both studies under this Research Topic point to important common factors that are involved in epigenetic modifications of mammalian genomes. It is well established that DNA methylation at promoters influences gene expression and the effects involve cooperative action of DNMT1 and HDAC1/HDAC2 in establishing and maintaining repressive histone modifications at their N-terminal tails (e.g., H3-K9 Me3) at methylated promoters (Burgers et al., 2002). The studies by Feng and Shen, and Singh et al. further implicate the involvement of epigenetic machinery (HDAC1 and DNMT1, respectively). It is noteworthy that a subset of SZ patients shows increased HDAC1 levels (Sharma et al., 2008), but it is not known whether these patients also have increased DNMT1 levels. In this context, investigations are needed to test DNMT1 overexpression effects on HDAC1 levels. Nevertheless, drug-based modulation of DNMT1 and HDAC1 levels/activity to normal ranges holds promise for better treatment of a subset of patients with SZ and possibly with other mental health disorders wherein either or both genes show dysregulation.
Author contributions
KM: Writing – original draft, Writing – review & editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Research in the author's laboratory was supported by grants from Scientific and Engineering Board, Department of Science and Technology, Department of Biotechnology and Indian Council of Medical Research.
Acknowledgments
Funds under the Centre for Human Disease Research initiative and OPERA scheme from BITS Pilani are thankfully acknowledged. The author thanks Anuhya Anne, Minali Singh, and Sumana Choudhury, for their contributions and their involvement in discussions at various stages.
Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
Agrawal, L., Korkutata, M., Vimal, S. K., Yadav, M., Bhattacharyya, S., Shiga, T., et al. (2020). Therapeutic potential of serotonin 4 receptor for chronic depression and its associated comorbidity in the gut. Neuropharmacology 166, 107969. doi: 10.1016/j.neuropharm.2020.107969
Boyda, H., Ho, A., Tse, L., Procyshyn, R., Yuen, J., Kim, D., et al. (2020). Differential effects of acute treatment with antipsychotic drugs on peripheral catecholamines. Front. Psychiatry. 11, 617428. doi: 10.3389/fpsyt.2020.617428
Burgers, W., Fuks, F., and Kouzarides, T. (2002). DNA methyltransferases get connected to chromatin. Trends Genet. 18, 275–277. doi: 10.1016/S0168-9525(02)02667-7
Corell, C. (2020). Current treatment options and emerging agents for schizophrenia. J. Clin. Psychiatry 81, MS19053BR.3C. doi: 10.4088/JCP.MS19053BR3C
Cropley, V., Klauser, P., Lenroot, R., Bruggemann, J., Sundram, S., Bousman, C., et al. (2017). Accelerated gray and white matter deterioration with age in schizophrenia. Am. J. Psychiatry 174, 286–295. doi: 10.1176/appi.ajp.2016.16050610
Farsi, Z., and Sheng, M. (2023). Molecular mechanisms of schizophrenia: insights from human genetics. Curr. Opin. Neurobiol. 81, 102731. doi: 10.1016/j.conb.2023.102731
George, M., Menze, E., Esmat, A., Tadros, M., and El-Demerdash, E. (2020). Potential therapeutic antipsychotic effects of naringin against ketamine-induced deficits in rats: involvement of Akt/GSK-3β and Wnt/β-catenin signaling pathways. Life Sci. 249, 117535. doi: 10.1016/j.lfs.2020.117535
Ghodke-Puranik, Y., Thorn, C., Lamba, J., Leeder, J., Song, W., Birnbaum, A., et al. (2013). Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenet. Genomics 23, 236–241. doi: 10.1097/FPC.0b013e32835ea0b2
Giovanni, G., and Deurwaerdère, P. (2016). New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders. Pharmacol. Ther. 157, 125–162. doi: 10.1016/j.pharmthera.2015.11.009
Huang, W., Li, Y.-H., Huang, S.-Q., Chen, H., Li, Z.-F., Li, X.-X., et al. (2021). Serum progesterone and testosterone levels in schizophrenia patients at different stages of treatment. J. Mol. Neurosci. 71, 1168–1173. doi: 10.1007/s12031-020-01739-w
Kehr, J., Yoshitake, T., Ichinose, F., Yoshitake, S., Kiss, B., Gyertyán, I., et al. (2018). Effects of cariprazine on extracellular levels of glutamate, GABA, dopamine, noradrenaline and serotonin in the medial prefrontal cortex in the rat phencyclidine model of schizophrenia studied by microdialysis and simultaneous recordings of locomotor activity. Psychopharmacology 235, 1593–1607. doi: 10.1007/s00213-018-4874-z
Kopecek, M., Svancer, P., Andrashko, V., Knytl, P., Kohutova, B., Kozeny, J., et al. (2019). Effect of vitamin D deficiency on BMI in patients treated with multi-acting receptor target antipsychotics. Neuro Endocrinol. Lett. 40, 75–78.
Korlatowicz, A., Kuśmider, M., Szalchta, M., Pabian, P., Solich, J., Dziedzicka-Wasylewska, M., et al. (2021). Identification of molecular markers of colazapin action in ketamine-induced cognitive impairment. Int. J. Mol. Sci. 22, 12203. doi: 10.3390/ijms222212203
Li, X.-L., Yu, Y., Hu, Y., Wu, H.-T., Li, X.-S., Chen, G.-Y., et al. (2022). Fibroblast growth factor 9 as a potential biomarker for schizophrenia. Front. Psychiatry. 25, 788677. doi: 10.3389/fpsyt.2022.788677
Merritt, K., McGuire, P., Egerton, A., and 1H-MRS in Schizophrenia Investigators Aleman, A. Block W. et al. (2021). Association of age, antipsychotic medication, and symptom severity in schizophrenia with proton magnetic resonance spectroscopy brain glutamate level: a mega-analysis of individual participant-level data. JAMA Psychiatry 78, 667–681. doi: 10.1001/jamapsychiatry.2021.0380
Mohan, K. (2022). DNMT1: catalytic and non-catalytic roles in different biological processes. Epigenomics 14, 629–643. doi: 10.2217/epi-2022-0035
Mohan, K., and Chaillet, J. (2013). Cell and molecular biology of DNA methyltransferase 1. Int. Rev. Cell Mol. Biol. 306, 1–42. doi: 10.1016/B978-0-12-407694-5.00001-8
Noto, M., Maes, M., Nunes, S., Ota, V., Cavalcante, D., Oliveira, G., et al. (2021). BDNF in antipsychotic naive first episode psychosis: effects of risperidone and the immune-inflammatory response system. J Psychiatr. Res. 141, 206–213. doi: 10.1016/j.jpsychires.2021.07.011
Ochiai, Y., Fujita, M., Hagino, Y., Kobayashi, K., Okiyama, R., Takahashi, K., et al. (2022). Therapeutic effects of quetiapine and 5-HT1A receptor agonism on hyperactivity in dopamine-deficient mice. Int. J. Mol. Sci. 23, 7436. doi: 10.3390/ijms23137436
Piriu, G., Torac, E., Gaman, L., Losif, L., Tivig, I., Delia, C., et al. (2015). Clozapine and risperidone influence on cortisol and estradiol levels in male patients with schizophrenia. J. Med. Life 8, 548–551.
Regen, F., Cosma, N.-C., Otto, L., Clemens, V., Saksone, L., Gellrich, J., et al. (2021). Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia. Mol. Psychiatry 26, 5417–5428. doi: 10.1038/s41380-020-0791-8
Revenga, M., Ibi, D., Cuddy, T., Toneatti, R., Kurita, M., Ijaz, T., et al. (2019). Chronic clozapine treatment restrains via HDAC2 the performance of mGlu2 receptor agonism in a rodent model of antipsychotic activity. Neuropsychopharmacology 44, 443–454. doi: 10.1038/s41386-018-0143-4
Saxena, S., Maroju, P., Choudhury, S., Voina, V., Naik, P., Gowdhaman, K., et al. (2021). Functional analysis of DNMT1 SNPs (rs222861 and rs2114724) associated with schizophrenia. Genetics Res. 31, 6698979. doi: 10.1155/2021/6698979
Servonnet, A., and Samaha, A. (2020). Antipsychotic-evoked dopamine supersensitivity. Neuropharmacology 163, 107630. doi: 10.1016/j.neuropharm.2019.05.007
Sharma, R., Grayson, D., and Gavin, D. (2008). Histone deacetylase 1 expression is increased in the prefrontal cortex of schizophrenia subjects: analysis of the national brain databank microarray collection. Schizophr. Res. 98, 111–117. doi: 10.1016/j.schres.2007.09.020
Tobolska, D., Wilczyński, K., Lorek, M., Mazgaj, E., Krysta, K., Gawlik, A., et al. (2016). Evaluation of the cortisol concentrations in patients with schizophrenia. Psychiatr. Danub. 28(Suppl-1), 162−164.
Trubetskoy, V., Pardiñas, A., Qi, T., Panagiotaropoulou, G., Awasthi, S., Bigdeli, T., et al. (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature 604, 502–508. doi: 10.1038/s41586-022-04434-5
Veldic, M., Guidotti, A., Maloku, E., Davis, J., and Costa, E. (2005). In psychosis, cortical interneurons overexpress DNA-methyltransferase 1. Proc. Natl. Acad. Sci. U.S.A. 102, 2152–2157. doi: 10.1073/pnas.0409665102
Winship, I., Dursun, S., Baker, G., Balista, P., Kandratavicius, L., Maia-de-Oliveria, J., et al. (2019). An overview of animal models related to schizophrenia. Can. J. Psychiatry 64, 5–17. doi: 10.1177/0706743718773728
Yoon, J., Maddock, R., Cui, E., Minzenberg, M., Niendam, T., Lesh, T., et al. (2020). Reduced visual cortex GABA in schizophrenia, a replication in a recent onset sample. Schizophr. Res. 215, 217–222. doi: 10.1016/j.schres.2019.10.025
Zhang, J.-X., and Lin, X. (2020). Changes in serum thyroid hormone levels in psychiatric patients treated with second-generation antipsychotics. Endokrynol. Pol. 71, 292–298. doi: 10.5603/EP.a2020.0036
Zhang, X., Xiao, W., Chen, K., Zhao, Y., Ye, F., Tang, X., et al. (2020). Serum epidermal growth factor is low in schizophrenia and not affected by antipsychotics alone or combined with electroconvulsive therapy. Front. Psychiatry. 3, 104. doi: 10.3389/fpsyt.2020.00104
Keywords: schizophrenia, DNMT1, programmed cell death, valproic acid, HDAC1, HDAC2, antipsychotic drug, DNMT1 inhibition
Citation: Mohan KN (2024) Editorial: New insights into investigating schizophrenia as a disorder of molecular pathways. Front. Mol. Neurosci. 17:1360616. doi: 10.3389/fnmol.2024.1360616
Received: 23 December 2023; Accepted: 02 January 2024;
Published: 10 January 2024.
Edited and reviewed by: Jean-Marc Taymans, Institut National de la Santé et de la Recherche Médicale (INSERM), France
Copyright © 2024 Mohan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Kommu Naga Mohan, a29tbXVtb2hhbiYjeDAwMDQwO2dtYWlsLmNvbQ==