Prioritization of differentially expressed genes in Substantia nigra transcriptomes of Parkinson's disease reveals key protein interactions and pathways

Abstract

Background: Parkinson's Disease (PD) is a progressive neurodegenerative disorder a major cause of disability in the elderly population. The search for potential biomarkers and drug targets continues as complete understanding of molecular mechanisms remain elusive. Whole genome expression profiling by microarray in combination with expression Quantitative Trait Loci (eQTL) analysis provides insight into the differential expression patterns of genes involved in the disease pathway. Objectives: To quantitatively and qualitatively characterize the Differentially Expressed Genes (DEGs) in substantia nigra of PD cases and to identify the possible effects of eQTLs on these DEGs. Methods: Whole genome expression profiling of substantia nigra was re-analyzed in nine datasets containing 181 samples which include 97 cases and 84 controls. This was followed by functional and eQTL analysis of the highly significant DEGs. Results: The study identified 424 DEGs consistently in two or more studies among which 34 genes were highly significant. 7 of these genes showed the presence of significant eQTLs in different brain regions including basal ganglia. Our study proposes diagnostic markers like GNAS and DDC; several therapeutic targets like PGC, RBM3, SLC18A2 and TH; and suggests regulatory partners which can be probable pharmacological modulators. Conclusions: The study prioritizes significant DEGs commonly found in multiple datasets, through functional and protein interaction network analyses. The study also brings out the modulatory effects of eQTLs on DEGs and proposes novel therapeutic targets.