INTEGRATED MOLECULAR NETWORK ANALYSIS REVEALS MYC, EIF4EBP1, AND NOS3 AS KEY DRIVERS OF CORTICAL ABNORMALITIES IN PKD–TSC OVERLAP

Abstract

PKD and TSC, characterized by different genetic disorders converge at a molecular level with the help of some common pathways in case of contiguous gene syndrome. TSC related brain abnormalities have been widely studied however, the contribution of PKD-associated pathways to abnormalities in the cerebral cortex remains obscure. In this study, a protein–protein interaction (PPI) network was created to investigate and analyze the shared molecular mechanisms and signaling pathways between PKD and TSC, putting a major focus on their potential roles in cortical development as well as the neurological function. Network analysis displayed a highly interconnected network centered on the hub proteins MYC, EIF4EBP1, and NOS3, indicating convergence of proliferative, translational, and neurovascular signaling pathways. Dysregulation of MYC was associated with altered neural progenitor proliferation and impaired neuronal differentiation, while persistent activation of EIF4EBP1 suggested abnormal mTOR dependent translational control affecting synaptic maturation. Additionally, the identification of NOS3 as a central network node highlighted a previously underappreciated role of neurovascular and metabolic dysregulation in PKD–TSC associated cortical pathology. Collectively, these findings propose a unified mechanistic model in which structural cortical abnormalities, synaptic hyperexcitability, and metabolic stress act in concert to drive neurological phenotypes such as epilepsy and cognitive impairment. This study provides novel systems-level insight into the cortical involvement of PKD–TSC overlap and identifies potential molecular targets for future therapeutic and experimental validation.