Gene Set Enrichment Analysis and Genetic Experiment Reveal Changes in Cell Signaling Pathways Induced by α-Synuclein Overexpression

Abnormal accumulation of alpha synuclein (α-Syn) in sporadic and familial Parkinson’s disease (PD) may be a key step in its pathogenesis. In this study, the expression matrix of the GSE95427 dataset after α-Syn overexpression in human glioma cell line H4 was obtained from the GEO database. We used the Gene Set Enrichment Analysis (GSEA) method to reanalyze this dataset to evaluate the possible functions of α-Syn. The results showed that the tumor necrosis factor alpha (TNF-α) signal was significantly activated in α-Syn-overexpressing cells, and oxidative phosphorylation signal, extracellular matrix signal, cell cycle related signal and fatty acid metabolism signal were significantly inhibited. Moreover, we employed the α-Syn-expressing transgenic Drosophila model of Parkinson’s disease and knocked-down eiger, a TNF superfamily ligand homologue, indicating that the TNF-α pathway plays a role in the common pathogenesis of synucleinopathies. Our analysis based on GSEA data provides more clues for a better understanding of α-Syn function.