REDUCED ACTIVITY OF PI3K/AKT/GSK3/MTOR PATHWAY IN RESPONSE TO NEGATIVE FOLD CHANGE OF FGF11 AND OTHER PHYSICALLY AND FUNCTIONALLY RELATED CALCIUM SIGNALING GENES IS PROBABLY CONTRIBUTING TO THE MAJOR SYMPTOMS OF PREMENSTRUAL DYSPHORIC DISORDER

Abstract

Premenstrual Dysphoric Disorder (PMDD) is a debilitating menstrual cycle-related mood disorder characterized by severe emotional and physical symptoms, including sadness, anxiety, and irritability. Although its etiology remains poorly understood, emerging evidence suggests a potential link between dysregulated calcium signaling and the major symptoms of PMDD. In this study, we employed a comprehensive bioinformatic approach to investigate the downregulation of the FGF11 gene as a contributing factor to the pathogenesis of PMDD in women. We conducted whole genome transcriptomics analysis on lymphoblastoid cell lines derived from control women and women affected by PMDD, identifying genes that were statistically dysregulated in PMDD patients. Subsequently, we constructed gene networks to unveil the intricate relationships among these differentially expressed genes. Our analysis revealed a significant downregulation of the FGF11 gene in PMDD-affected individuals. FGF11, a member of the fibroblast growth factor (FGF) family, has been linked to calcium signaling regulation, which prompted further investigation. The dysregulated genes in PMDD were found to encode proteins that participate in the PI3K/AKT/GSK3/mTOR signaling pathway, a key regulator of cellular growth, proliferation, and survival. Furthermore, these dysregulated genes were involved in calcium homeostasis, emphasizing the potential role of calcium signaling in PMDD pathophysiology. We established protein-protein interactions among the products of the dysregulated genes in PMDD patients, highlighting the complex interplay within this network. Our findings suggest that downregulation of the FGF11 gene is associated with the dysregulation of the PI3K-Akt pathway and disruption of calcium homeostasis. These molecular alterations likely contribute to the manifestation of the major symptoms of PMDD, including sadness, anxiety, and irritability. Understanding the involvement of the PI3K/AKT/GSK3/mTOR pathway and calcium signaling in PMDD may pave the way for targeted interventions and therapeutic strategies to alleviate the burden of this disorder. Further experimental validation and clinical studies are warranted to confirm these findings and explore potential treatment options.