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; Claudia Manzoni; Sara Bandres-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; Lorene Mottier; Alessandra Carrella; Dezirae Beck-Schneider; Andreia D. Magalhães; Caroline Aemisegger; Alexandre P.A. Theocharides; Zhanyun Fan; Jordan D. Marks; Sarah C. Hopp; Andrey Y. Abramov; Patrick A. Lewis; Mina Ryten; John Hardy; Bradley T. Hyman; Adriano Aguzzi

doi:10.1016/j.celrep.2021.109189

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, Claudia Manzoni, Sara Bandres-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, Lorene Mottier, Alessandra CarrellaDezirae Beck-Schneider, Andreia D. Magalhães, Caroline Aemisegger, Alexandre P.A. Theocharides, Zhanyun Fan, Jordan D. Marks, Sarah C. Hopp, Andrey Y. Abramov, Patrick A. Lewis, Mina Ryten, John Hardy, Bradley T. Hyman, Adriano Aguzzi

Producción científica: Article › revisión exhaustiva

6 Citas (Scopus)

Resumen

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.

Idioma original	English (US)
Número de artículo	109189
Publicación	Cell Reports
Volumen	35
N.º	10
DOI	https://doi.org/10.1016/j.celrep.2021.109189
Estado	Published - jun 8 2021

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2021.109189

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Kara, E., Crimi, A., Wiedmer, A., Emmenegger, M., Manzoni, C., Bandres-Ciga, S., D'Sa, K., Reynolds, R. H., Botía, J. A., Losa, M., Lysenko, V., Carta, M., Heinzer, D., Avar, M., Chincisan, A., Blauwendraat, C., García-Ruiz, S., Pease, D., Mottier, L., ... Aguzzi, A. (2021). An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of α-synuclein. Cell Reports, 35(10), Artículo 109189. https://doi.org/10.1016/j.celrep.2021.109189

Kara, E, Crimi, A, Wiedmer, A, Emmenegger, M, Manzoni, C, Bandres-Ciga, S, D'Sa, K, Reynolds, RH, Botía, JA, Losa, M, Lysenko, V, Carta, M, Heinzer, D, Avar, M, Chincisan, A, Blauwendraat, C, García-Ruiz, S, Pease, D, Mottier, L, Carrella, A, Beck-Schneider, D, Magalhães, AD, Aemisegger, C, Theocharides, APA, Fan, Z, Marks, JD, Hopp, SC, Abramov, AY, Lewis, PA, Ryten, M, Hardy, J, Hyman, BT & Aguzzi, A 2021, 'An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of α-synuclein', Cell Reports, vol. 35, n.º 10, 109189. https://doi.org/10.1016/j.celrep.2021.109189

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title = "An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of α-synuclein",

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.",

keywords = "Braak hypothesis, GWAS, ITGA8, high-throughput screen, siRNA, weighted gene co-expression network analysis, weighted protein-protein network interaction analysis, α-synuclein",

author = "Eleanna Kara and Alessandro Crimi and Anne Wiedmer and Marc Emmenegger and Claudia Manzoni and Sara Bandres-Ciga and Karishma D'Sa and Reynolds, {Regina H.} and Bot{\'i}a, {Juan A.} and Marco Losa and Veronika Lysenko and Manfredi Carta and Daniel Heinzer and Merve Avar and Andra Chincisan and Cornelis Blauwendraat and Sonia Garc{\'i}a-Ruiz and Daniel Pease and Lorene Mottier and Alessandra Carrella and Dezirae Beck-Schneider and Magalh{\~a}es, {Andreia D.} and Caroline Aemisegger and Theocharides, {Alexandre P.A.} and Zhanyun Fan and Marks, {Jordan D.} and Hopp, {Sarah C.} and Abramov, {Andrey Y.} and Lewis, {Patrick A.} and Mina Ryten and John Hardy and Hyman, {Bradley T.} and Adriano Aguzzi",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = jun,

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doi = "10.1016/j.celrep.2021.109189",

language = "English (US)",

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AU - Kara, Eleanna

AU - Crimi, Alessandro

AU - Wiedmer, Anne

AU - Emmenegger, Marc

AU - Manzoni, Claudia

AU - Bandres-Ciga, Sara

AU - D'Sa, Karishma

AU - Reynolds, Regina H.

AU - Botía, Juan A.

AU - Losa, Marco

AU - Lysenko, Veronika

AU - Carta, Manfredi

AU - Heinzer, Daniel

AU - Avar, Merve

AU - Chincisan, Andra

AU - Blauwendraat, Cornelis

AU - García-Ruiz, Sonia

AU - Pease, Daniel

AU - Mottier, Lorene

AU - Carrella, Alessandra

AU - Beck-Schneider, Dezirae

AU - Magalhães, Andreia D.

AU - Aemisegger, Caroline

AU - Theocharides, Alexandre P.A.

AU - Fan, Zhanyun

AU - Marks, Jordan D.

AU - Hopp, Sarah C.

AU - Abramov, Andrey Y.

AU - Lewis, Patrick A.

AU - Ryten, Mina

AU - Hardy, John

AU - Hyman, Bradley T.

AU - Aguzzi, Adriano

PY - 2021/6/8

Y1 - 2021/6/8

N2 - 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.

AB - 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.

KW - Braak hypothesis

KW - GWAS

KW - ITGA8

KW - high-throughput screen

KW - siRNA

KW - weighted gene co-expression network analysis

KW - weighted protein-protein network interaction analysis

KW - α-synuclein

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DO - 10.1016/j.celrep.2021.109189

M3 - Article

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SN - 2211-1247

VL - 35

JO - Cell Reports

JF - Cell Reports

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M1 - 109189

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

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