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

Research output: Contribution to journalArticle

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.

Details

Authors
  • ADGC, Alzheimer’s Disease Neuroimaging Initiative
Organisations
External organisations
  • University of Lille Nord de France
  • Washington University in St. Louis
  • Brigham Young University
  • Institut Gustave Roussy
  • Mayo Clinic Minnesota
  • University of Pennsylvania
  • Johns Hopkins University School of Medicine
  • Duke University
  • Washington University School of Medicine
  • Sahlgrenska University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Neurosciences
Original languageEnglish
Pages (from-to)955-966
Number of pages12
JournalActa Neuropathologica
Volume133
Issue number6
Early online date2016 Dec 8
Publication statusPublished - 2017
Publication categoryResearch
Peer-reviewedYes