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Open Access 01-06-2017 | Original Paper

Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism

Authors: Julien Chapuis, Amandine Flaig, Benjamin Grenier-Boley, Fanny Eysert, Virginie Pottiez, Gaspard Deloison, Alexandre Vandeputte, Anne-Marie Ayral, Tiago Mendes, Shruti Desai, Alison M. Goate, John S. K. Kauwe, Florence Leroux, Adrien Herledan, Florie Demiautte, Charlotte Bauer, Fréderic Checler, Ronald C. Petersen, Kaj Blennow, Henrik Zetterberg, Lennart Minthon, Vivianna M. Van Deerlin, Virginia Man-Yee Lee, Leslie M. Shaw, John Q. Trojanowski, Marilyn Albert, Abhay Moghekar, Richard O’Brien, Elaine R. Peskind, Nicolas Malmanche, Gerard D. Schellenberg, Pierre Dourlen, Ok-Ryul Song, Carlos Cruchaga, Philippe Amouyel, Benoit Deprez, Priscille Brodin, Jean-Charles Lambert, ADGC, Alzheimer’s Disease Neuroimaging Initiative

Published in: Acta Neuropathologica | Issue 6/2017

Abstract

Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.

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Title: Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism
Authors: Julien Chapuis
Amandine Flaig
Benjamin Grenier-Boley
Fanny Eysert
Virginie Pottiez
Gaspard Deloison
Alexandre Vandeputte
Anne-Marie Ayral
Tiago Mendes
Shruti Desai
Alison M. Goate
John S. K. Kauwe
Florence Leroux
Adrien Herledan
Florie Demiautte
Charlotte Bauer
Fréderic Checler
Ronald C. Petersen
Kaj Blennow
Henrik Zetterberg
Lennart Minthon
Vivianna M. Van Deerlin
Virginia Man-Yee Lee
Leslie M. Shaw
John Q. Trojanowski
Marilyn Albert
Abhay Moghekar
Richard O’Brien
Elaine R. Peskind
Nicolas Malmanche
Gerard D. Schellenberg
Pierre Dourlen
Ok-Ryul Song
Carlos Cruchaga
Philippe Amouyel
Benoit Deprez
Priscille Brodin
Jean-Charles Lambert
ADGC, Alzheimer’s Disease Neuroimaging Initiative
Publication date: 01-06-2017
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 6/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-016-1652-z

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Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism

Abstract

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Abstract

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