Chapuis Julien, Flaig Amandine, Grenier-Boley Benjamin, Eysert Fanny, Pottiez Virginie, Deloison Gaspard, Vandeputte Alexandre, Ayral Anne-Marie, Mendes Tiago, Desai Shruti, Goate Alison M, Kauwe John S K, Leroux Florence, Herledan Adrien, Demiautte Florie, Bauer Charlotte, Checler Fréderic, Petersen Ronald C, Blennow Kaj, Zetterberg Henrik, Minthon Lennart, Van Deerlin Vivianna M, Lee Virginia Man-Yee, Shaw Leslie M, Trojanowski John Q, Albert Marilyn, Moghekar Abhay, O'Brien Richard, Peskind Elaine R, Malmanche Nicolas, Schellenberg Gerard D, Dourlen Pierre, Song Ok-Ryul, Cruchaga Carlos, Amouyel Philippe, Deprez Benoit, Brodin Priscille, Lambert Jean-Charles
Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, 59000, Lille, France.
Acta Neuropathol. 2017 Jun;133(6):955-966. doi: 10.1007/s00401-016-1652-z. Epub 2016 Dec 8.
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.
全基因组关联研究（GWAS）已确定了19个阿尔茨海默病（AD）的易感基因座。然而，了解这些基因如何参与AD的病理生理过程是“后GWAS”时代的主要挑战之一。至少有123个基因位于这19个易感基因座内；因此，传统方法（逐个研究基因）既不节省时间也不经济高效。因此，我们开发了一种全基因组、高内涵的siRNA筛选方法，并用于评估基因低表达对APP代谢的功能影响。我们发现832个基因调节APP代谢。其中8个基因位于AD易感基因座内。只有FERMT2（一种β3整合素共激活因子）也与2886例AD病例的脑脊液Aβ肽水平变化显著相关。最后，我们表明FERMT2的低表达通过提高细胞表面成熟APP的水平并促进其再循环来增加Aβ肽的产生。总体而言，我们的数据表明FERMT2通过调节APP代谢和Aβ肽产生来调节AD风险。
