Summary Neuropathological and experimental evidence suggests that the cell-to-cell transfer of α-synuclein has an important role in the pathogenesis of Parkinson’s disease (PD). However, the mechanism underlying this phenomenon is not fully understood. We undertook a small interfering RNA (siRNA), genome-wide screen to identify genes regulating the cell-to-cell transfer of α-synuclein. A genetically encoded reporter, GFP-2A-αSynuclein-RFP, suitable for separating donor and recipient cells, was transiently transfected into HEK cells stably overexpressing α-synuclein. We find that 38 genes regulate the transfer of α-synuclein-RFP, one of which is ITGA8, a candidate gene identified through a recent PD genome-wide association study (GWAS). Weighted gene co-expression network analysis (WGCNA) and weighted protein-protein network interaction analysis (WPPNIA) show that those hits cluster in networks that include known PD genes more frequently than expected by random chance. The findings expand our understanding of the mechanism of α-synuclein spread.
Graphical abstract
Highlights • 38 genes regulate the cell-to-cell transfer of α-synuclein • Those genes participate in the same networks as known Parkinson’s disease (PD) genes • Knockdown of selected genes affects mitochondrial ΔΨm similarly to recessive PD genes • The “prionoid” hypothesis likely has an important role in the pathogenesis of PD
Kara et al. undertook a high-throughput screen that identified 38 genes that regulate the cell-to-cell transfer of α-synuclein. Those genes participate in the same networks as known Parkinson’s disease Mendelian and risk genes. This work provides a framework for a gene-discovery strategy in complex diseases.