Dataset Information

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

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 ?3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid A? peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases A? 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 A? peptide production.

SUBMITTER: Chapuis J

PROVIDER: S-EPMC5427165 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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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 J Flaig Amandine A Grenier-Boley Benjamin B Eysert Fanny F Pottiez Virginie V Deloison Gaspard G Vandeputte Alexandre A Ayral Anne-Marie AM Mendes Tiago T Desai Shruti S Goate Alison M AM Kauwe John S K JSK Leroux Florence F Herledan Adrien A Demiautte Florie F Bauer Charlotte C Checler Fréderic F Petersen Ronald C RC Blennow Kaj K Zetterberg Henrik H Minthon Lennart L Van Deerlin Vivianna M VM Lee Virginia Man-Yee VM Shaw Leslie M LM Trojanowski John Q JQ Albert Marilyn M Moghekar Abhay A O'Brien Richard R Peskind Elaine R ER Malmanche Nicolas N Schellenberg Gerard D GD Dourlen Pierre P Song Ok-Ryul OR Cruchaga Carlos C Amouyel Philippe P Deprez Benoit B Brodin Priscille P Lambert Jean-Charles JC

Acta neuropathologica 20161208 6

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 ...[more]

PMID: 27933404

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Dataset Information

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

Publications

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

Similar Datasets

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