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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

Chapuis, Julien; Flaig, Amandine; Grenier-Boley, Benjamin; Eysert, Fanny; Pottiez, Virginie; Deloison, Gaspard; Vandeputte, Alexandre; Ayral, Anne Marie; Mendes, Tiago and Desai, Shruti, et al. (2017) In Acta Neuropathologica 133(6). p.955-966
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... (More)

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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@article{bc82cd6d-e1dc-4a0a-86a7-10af73b77963,
  abstract     = {<p>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.</p>},
  author       = {Chapuis, Julien and Flaig, Amandine and Grenier-Boley, Benjamin and Eysert, Fanny and Pottiez, Virginie and Deloison, Gaspard and Vandeputte, Alexandre and Ayral, Anne Marie and Mendes, Tiago and Desai, Shruti and Goate, Alison M. and Kauwe, John S K and Leroux, Florence and Herledan, Adrien and Demiautte, Florie and Bauer, Charlotte and Checler, Fréderic and Petersen, Ronald C. and Blennow, Kaj and Zetterberg, Henrik and Minthon, Lennart and van Deerlin, Vivianna M. and Lee, Virginia Man Yee and Shaw, Leslie M. and Trojanowski, John Q. and Albert, Marilyn and Moghekar, Abhay and O’Brien, Richard and Peskind, Elaine R. and Malmanche, Nicolas and Schellenberg, Gerard D. and Dourlen, Pierre and Song, Ok Ryul and Cruchaga, Carlos and Amouyel, Philippe and Deprez, Benoit and Brodin, Priscille and Lambert, Jean Charles and , },
  issn         = {0001-6322},
  language     = {eng},
  number       = {6},
  pages        = {955--966},
  publisher    = {Springer},
  series       = {Acta Neuropathologica},
  title        = {Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism},
  url          = {http://dx.doi.org/10.1007/s00401-016-1652-z},
  volume       = {133},
  year         = {2017},
}