Transcriptome analysis to explore the mechanism of downregulated TNIK influencing the effect of risperidone

Ruixue Yuan; Yaojing Li; Xiangyi Li; Yingmei Fu; Ailing Ning; Dongxiang Wang; Ran Zhang; Shunying Yu; Qingqing Xu

doi:10.3389/fphar.2024.1431923

Transcriptome analysis to explore the mechanism of downregulated TNIK influencing the effect of risperidone

Front Pharmacol. 2024 Aug 23:15:1431923. doi: 10.3389/fphar.2024.1431923. eCollection 2024.

Authors

Ruixue Yuan¹, Yaojing Li², Xiangyi Li³, Yingmei Fu¹, Ailing Ning¹, Dongxiang Wang¹, Ran Zhang¹, Shunying Yu¹, Qingqing Xu¹

Affiliations

¹ Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² 958 Hospital of PLA ARMY, Chongqing, China.
³ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.

Abstract

Background: Risperidone is one of the most reliable and effective antipsychotics for schizophrenia treatment. However, the mechanism of action of risperidone is not yet fully understood. Traf2 and Nck-interacting protein kinase (TNIK), a schizophrenia susceptibility gene, is associated with risperidone treatment response. Our previous in vitro experiments confirmed that downregulated TNIK affected the effect of risperidone on downstream targets. However, the effect of downregulated TNIK on risperidone-induced molecular expression remains to be further explored.

Methods: Transcriptome analysis was performed on U251 cells subjected to risperidone, TNIK siRNA, and no treatment, respectively. Compared to the no-treatment group, two groups of DEGs were screened out and then intersected with the schizophrenia-related genes to screen the cross-talk genes. Those DEGs were analyzed using GO and KEGG. STRING and Cytoscape were used to construct a protein-protein interaction (PPI) network for the cross-talk gene.

Results: The results showed that the parathyroid hormone synthesis, secretion, and action were significantly enriched after risperidone treatment. Downregulated TNIK could have an impact on the collagen-containing extracellular matrix, signaling receptor activator activity, and PI3K-Akt signaling pathway. Interestingly, bone mineralization function and calcium signaling pathway were enriched in the cross-talk genes. Additionally, FGFR2, FGF1, and FGFR might be the potential targets for TNIK affecting the effects of risperidone.

Conclusion: The study indicated that risperidone primarily influences functions and/or pathways associated with bone metabolism, potentially contributing to the adverse effect of osteoporosis. Our study may offer a novel perspective on investigating the mechanisms underlying the adverse effects of risperidone.

Keywords: Traf2 and Nck-interacting protein kinase (TNIK); bone mineralization; protein-protein interaction; risperidone; transcriptome analysis.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported financially by the National Natural Science Foundation of China (No.82401760, No.81971257), the General Program of Shanghai Mental Health Center “Academic project” (2021-YJ04), the Fundamental Research Funds for the Central Universities (YG2024QNB31), the General Program of Shanghai Mental Health Center “Academic project” (2021-YJ07), the Key Program of Shanghai Mental Health Center “Academic project” (2023zd02), and the Key Program of the Clinical Research Center of Shanghai Mental Health Center (CRC2021ZD02).