Title : PDCD4-mediated regulatory networks in progressive supranuclear palsy: A multi-omics analysis reveals novel therapeutic targets
Abstract:
Background: Progressive Supranuclear Palsy (PSP) is a devastating tauopathy characterized by tau aggregation, neuronal loss, and limited therapeutic options. While tau pathology is central to PSP, the regulatory mechanisms governing disease progression remain poorly understood.
Methods: We conducted comprehensive multi-omics analysis using PSP datasets GSE186921 (miRNA expression) and GSE255902 (mRNA expression from hiPSC-derived neurons). Differential expression analysis identified key molecular signatures, followed by protein-protein interaction (PPI) network construction using STRING database and pathway enrichment analysis via Enrichr platform. We constructed a PDCD4-centered regulatory network to elucidate its role in PSP pathogenesis.
Results: Differential expression analysis revealed 1,050 mRNA changes (739 upregulated, 311 downregulated) and 8 miRNA alterations (7 upregulated, 1 downregulated) in PSP. Notably, hsa-miR-206 showed significant upregulation (log2FC = 1.8, p = 0.02) with PDCD4 as a key target. PPI network analysis of differentially expressed genes revealed dense connectivity (PPI enrichment p < 1.0e-16) with AKT1, BDNF, and EGF as major hubs. A focused PDCD4-centered network of 10 proteins demonstrated highly statistical significance (p = 8.8 × 10??) and 4-fold enrichment over random expectation. Pathway enrichment analysis confirmed involvement in apoptosis regulation, tau phosphorylation, and PI3K/AKT signaling pathways. The hsa-miR-206/PDCD4 axis offers potential as a biomarker and therapeutic target for PSP due to its druggability and accessibility in biofluids.
Conclusions: Our findings reveal PDCD4 as a critical regulatory node in PSP pathogenesis, positioned at the intersection of translational control, survival signaling, and tau pathology. The hsa-miR-206/PDCD4 axis represents a novel therapeutic target, while the integrated network provides mechanistic insights into PSP molecular pathology and potential intervention strategies.
Keywords: Progressive Supranuclear Palsy, PDCD4, protein-protein interaction networks, miRNA regulation, tau pathology, neurodegeneration.
