An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of a-synuclein

Kara, E and Crimi, A and Wiedmer, A and Emmenegger, M and Manzoni, C and Bandres-Ciga, S and D’Sa, K and Reynolds, RH and Botía, JA and Losa, M and Lysenko, V and Carta, M and Heinzer, D and Avar, M and Chincisan, A and Blauwendraat, C and Ruiz, SG and Pease, D and Mottier, L and Carrella, A and Schneider, D and Magalhaes, A and Aemisegger, C and Theocharides, APA and Fan, Z and Marks, JD and Hopp, SC and Lewis, P and Ryten, Mina and Hardy, John and Hyman, Bradley T and Aguzzi, Adriano (2019) An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of a-synuclein. Cold Spring Harbor Laboratory, bioRxiv. (Submitted)

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Official URL: https://doi.org/10.1101/2019.12.23.886838

Abstract

Neuropathological and experimental evidence suggests that the cell-to-cell transfer of a-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 an siRNA, genome-wide high throughput screen to identify genes regulating the cell-to-cell transfer of a-synuclein. We transiently transfected HEK cells stably overexpressing a-synuclein with a construct encoding GFP-2a-aSynuclein-RFP. The cells expressing a-synuclein-RFP through transfection were double positive for GFP and RFP fluorescence, whereas the cells receiving it through transfer were positive only for RFP fluorescence. The amount of a-synuclein transfer was quantified by high content microscopy. A series of unbiased screens confirmed the involvement of 38 genes in the regulation of a-synuclein-RFP transfer. One of those hits was ITGA8, a candidate gene recently identified through a large PD genome wide association study (GWAS). Weighted gene co-expression network analysis (WGCNA) and weighted protein-protein network interaction analysis (WPPNIA) showed that the hits clustered in networks that included known PD Mendelian and GWAS risk genes more frequently than expected than random chance. Given the genetic overlap between a-synuclein transfer and PD, those findings provide supporting evidence for the importance of the cell-to-cell transfer of a-synuclein in the pathogenesis of PD, and expand our understanding of the mechanism of a-synuclein spread.

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