Integrated RNA-Sequencing Profiling and Molecular Docking to Identify Key Genes, pathways and Drug Targets for Frontotemporal Dementia

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disease marked by progressive degeneration of the brain’s frontal and temporal lobes, resulting in behavioral and cognitive impairments. There are no current disease-modifying therapies for FTD. This study analyzed RNA sequencing datasets to identify differentially expressed genes (DEGs) and dysregulated molecular pathways contributing to FTD pathogenesis. Protein-protein interaction network analysis revealed key genes-RPL13A, MED1, MRTO4, RPL12, EIF3G, EIF5A, CDH1, IGF1, CD44, and SOD1-with strong centrality in disease pathways. Molecular docking studies demonstrated significant binding affinities of phytochemicals to FTD-associated proteins. Notably the phytochemical epigallocatechin gallate shows binding affinity with more than one FTD proteins: 4UG0, 8FKR, 4V6X, 6YBS, 3CPF, 7WRQ and 1UUH with docking score of -8, -6.7, -7, -6, -7.7, -6.9 and -7.2 kcal/mol respectively. The hesperetin shows binding free energy of -9.4 kcal/mol with 1RJK.  The phytochemical hesperetin, luteolin, naringenin, apigenin and epicatechin shows significant binding towards 1RJK with the binding free energy of -9.4, -9.3, -9.2, -9.1 and -8.5 kcal/mol respectively. Toxicity predictions identified epicatechin as a favorable drug candidate, demonstrating low toxicity and a benign safety profile. Our findings highlight the power of omics-driven and computational approaches to identify novel therapeutic agents for FTD.