Integrative analysis of substantia nigra transcriptomes from 22 PD and 22 controls across three GEO datasets identified 85 consensus differentially expressed mRNAs—including molecular chaperones (DNAJB1, HSPA1B/L), dopaminergic markers (TH, SLC6A3), ECM components—and 20 PPI hub genes, with…

The study prioritizes biologically plausible biomarkers and therapeutic targets tied to proteostasis and mitochondrial/dopaminergic dysfunction in PD, offering a focused candidate list for follow-up validation and target-driven drug discovery despite being limited to post-mortem,…

This study employed an integrative bioinformatics approach to identify key molecular signatures in Parkinson's disease (PD) by analyzing substantia nigra transcriptomes from 22 PD patients and 22 healthy controls (HCs) across three Gene Expression Omnibus (GEO) datasets. Using DESeq2, edgeR, and limma, we identified 85 consensuses differentially expressed mRNA (DEmRNAs) (23 up-regulated and 62 down-regulated), including key players in PD pathogenesis such as molecular chaperones (DNAJB1, HSPA1B/L), dopaminergic markers (TH, SLC6A3), and extracellular matrix components (COL5A1, LAMB1). Functional enrichment analyses revealed up-regulated pathways in PI3K-Akt signaling and extracellular matrix organization, while down-regulated genes were enriched in dopaminergic synapse and mitochondrial function pathways. Protein-protein interaction (PPI) network analysis identified 20 hub genes, with DNAJB1, TH, KCNJ6, and SLC6A3 emerging as central regulators. Notably, we discovered novel candidate's mRNAs alongside validated PD-associated genes, highlighting both degenerative processes and compensatory mechanisms. These findings provide a comprehensive molecular framework for PD pathogenesis, offering potential biomarkers and therapeutic targets for further investigation.