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

Authors :
Cornelis Blauwendraat
John Hardy
Alessandro Crimi
Regina H. Reynolds
Mina Ryten
Dezirae Schneider
Sara Bandres-Ciga
Eleanna Kara
Daniel Heinzer
Alexandre Theocharides
Claudia Manzoni
Juan A. Botía
Marco Losa
Jordan D. Marks
Veronika Lysenko
Patrick A. Lewis
Merve Avar
Bradley T. Hyman
Sarah C. Hopp
Daniel Patrick Pease
Zhanyun Fan
Alessandra Carrella
Anne Wiedmer
Marc Emmenegger
Karishma D’Sa
Andra Chincisan
Andreia D. Magalhães
Lorene Mottier
Adriano Aguzzi
Manfredi Carta
Caroline Aemisegger
Sonia Garcia Ruiz
Publication Year :
2019
Publisher :
Cold Spring Harbor Laboratory, 2019.

Abstract

SummaryNeuropathological 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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....7e4071e59018abf3fcdf39a305b58151
Full Text :
https://doi.org/10.1101/2019.12.23.886838