Cargando…
Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism
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 susceptibil...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427165/ https://www.ncbi.nlm.nih.gov/pubmed/27933404 http://dx.doi.org/10.1007/s00401-016-1652-z |
_version_ | 1783235616977190912 |
---|---|
author | 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 |
author_facet | 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 |
author_sort | Chapuis, Julien |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-016-1652-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5427165 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-54271652017-05-26 Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism 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 Acta Neuropathol Original Paper 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-016-1652-z) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2016-12-08 2017 /pmc/articles/PMC5427165/ /pubmed/27933404 http://dx.doi.org/10.1007/s00401-016-1652-z Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Paper 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 Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism |
title | Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism |
title_full | Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism |
title_fullStr | Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism |
title_full_unstemmed | Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism |
title_short | Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism |
title_sort | genome-wide, high-content sirna screening identifies the alzheimer’s genetic risk factor fermt2 as a major modulator of app metabolism |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427165/ https://www.ncbi.nlm.nih.gov/pubmed/27933404 http://dx.doi.org/10.1007/s00401-016-1652-z |
work_keys_str_mv | AT chapuisjulien genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT flaigamandine genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT grenierboleybenjamin genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT eysertfanny genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT pottiezvirginie genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT deloisongaspard genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT vandeputtealexandre genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT ayralannemarie genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT mendestiago genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT desaishruti genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT goatealisonm genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT kauwejohnsk genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT lerouxflorence genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT herledanadrien genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT demiautteflorie genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT bauercharlotte genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT checlerfrederic genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT petersenronaldc genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT blennowkaj genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT zetterberghenrik genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT minthonlennart genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT vandeerlinviviannam genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT leevirginiamanyee genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT shawlesliem genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT trojanowskijohnq genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT albertmarilyn genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT moghekarabhay genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT obrienrichard genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT peskindelainer genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT malmanchenicolas genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT schellenberggerardd genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT dourlenpierre genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT songokryul genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT cruchagacarlos genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT amouyelphilippe genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT deprezbenoit genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT brodinpriscille genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT lambertjeancharles genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism AT genomewidehighcontentsirnascreeningidentifiesthealzheimersgeneticriskfactorfermt2asamajormodulatorofappmetabolism |