An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of α-synuclein
Eleanna Kara, Alessandro Crimi, Anne Wiedmer, Marc Emmenegger, C. Manzoni, Sara Bandrés‐Ciga, Karishma D’Sa, Regina H. Reynolds, Juan A. Botía, Marco Losa, Veronika Lysenko, Manfredi Carta, Daniel Heinzer, Merve Avar, Andra Chincisan, Cornelis Blauwendraat, Sonia García-Ruiz, Daniel Pease, Lorène Mottier, Alessandra Carrella, Dezirae Beck-Schneider, Andreia D. Magalhães, Caroline Aemisegger, Alexandre Theocharides, Zhanyun Fan, Jordan D. Marks, Sarah C. Hopp, Andrey Y. Abramov, Patrick A. Lewis, Mina Ryten, John Hardy, Bradley T. Hyman, Adriano Aguzzi
Abstract
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.