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

Cell Rep. 2021 Jun 8;35(10):109189. doi: 10.1016/j.celrep.2021.109189.

Authors

Eleanna Kara¹, Alessandro Crimi², Anne Wiedmer², Marc Emmenegger², Claudia Manzoni³, Sara Bandres-Ciga⁴, Karishma D'Sa⁵, Regina H Reynolds⁶, Juan A Botía⁷, Marco Losa², Veronika Lysenko⁸, Manfredi Carta², Daniel Heinzer², Merve Avar², Andra Chincisan², Cornelis Blauwendraat⁴, Sonia García-Ruiz⁶, Daniel Pease², Lorene Mottier², Alessandra Carrella², Dezirae Beck-Schneider², Andreia D Magalhães², Caroline Aemisegger⁹, Alexandre P A Theocharides⁸, Zhanyun Fan¹⁰, Jordan D Marks¹¹, Sarah C Hopp¹², Andrey Y Abramov¹³, Patrick A Lewis¹⁴, Mina Ryten⁶, John Hardy¹⁵, Bradley T Hyman¹⁰, Adriano Aguzzi¹⁶

Affiliations

¹ Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland; Department of Neurodegenerative disease, University College London, London WC1N 3BG, UK.
² Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland.
³ Department of Pharmacology, University College London School of Pharmacy, London WC1N 1AX, UK; School of Pharmacy, University of Reading, Reading RG6 6AP, UK.
⁴ Laboratory of Neurogenetics, National Institutes of Health, Bethesda, MD 20814, USA.
⁵ The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK.
⁶ Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.
⁷ Department of Neurodegenerative disease, University College London, London WC1N 3BG, UK; Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia 30100, Spain.
⁸ Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich 8091, Switzerland.
⁹ Center for Microscopy and Image Analysis, University of Zurich, Zurich 8057, Switzerland.
¹⁰ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
¹¹ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
¹² Department of Pharmacology, UT Health San Antonio, San Antonio, TX 78229, USA; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX 78229, USA.
¹³ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
¹⁴ Department of Neurodegenerative disease, University College London, London WC1N 3BG, UK; School of Pharmacy, University of Reading, Reading RG6 6AP, UK; Department of Comparative Biomedical Sciences, Royal Veterinary College, London NW1 0TU, UK.
¹⁵ Department of Neurodegenerative disease, University College London, London WC1N 3BG, UK; UK Dementia Research Institute, University College London, London WC1N 3BG, UK; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, 1 Wakefield Street, London WC1N 1PJ, UK; Institute for Advanced Study, the Hong Kong University of Science and Technology, Hong Kong SAR, China.
¹⁶ Institute of Neuropathology, University of Zurich and University Hospital Zurich, Zurich 8091, Switzerland. Electronic address: adriano.aguzzi@usz.ch.

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.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Communication / physiology*
Genome-Wide Association Study / methods*
Humans
Protein Interaction Maps / physiology*
alpha-Synuclein / metabolism*

Substances

alpha-Synuclein

Abstract

Publication types

MeSH terms

Substances

Grants and funding