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Acta Neuropathol. 2017 Jun;133(6):955-966. doi: 10.1007/s00401-016-1652-z. Epub 2016 Dec 8.

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

Author information

1
Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France. julien.chapuis@pasteur-lille.fr.
2
Laboratoire d'Excellence Distalz, Univ. Lille, Unité INSERM 1167, Institut Pasteur de Lille, BP 245, 1 rue du professeur Calmette, 59000, Lille cedex, France.
3
Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, 59000, Lille, France.
4
Univ. Lille, INSERM, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, 59000, Lille, France.
5
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
6
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
7
Departments of Biology and Neuroscience, Brigham Young University, Provo, USA.
8
Laboratoire d'Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, IPMC, France, 660 route des Lucioles, Sophia-Antipolis, 06560, Valbonne, France.
9
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
10
Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgren's University Hospital, Mölndal, Gothenburg, Sweden.
11
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
12
Clinical Memory Research Unit, Dept of Clinical Sciences, Lund University, Lund, Sweden.
13
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
14
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
15
Department of Neurology, Duke Medical Center, Box 2900, Durham, NC, 27710, USA.
16
Departments of Psychiatry and Behavioral Sciences, Veterans Affairs Northwest Network Mental Illness Research, Education, and Clinical Center, University of Washington School of Medicine, Seattle, USA.
17
Stellar-Chance Laboratories, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.

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.

PMID:
27933404
PMCID:
PMC5427165
DOI:
10.1007/s00401-016-1652-z
[Indexed for MEDLINE]
Free PMC Article

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